JPH032161A - 1,4-dihydropyridine derivative - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I [Ar<1> and Ar<2> are (substituted)aromatic hydrocarbon group or (substituted)aromatic heterocyclic group, R<1> is CO2R<2>, SO2R<3>, COR<4>, CONR<5>2, CN or NO2 (R<2> is H, 2-10C straight-chain, branched or cyclic saturated or unsaturated hydrocarbon group which may be substituted; R<3>, R<4>, R<5> are lower alkyl; R<4> is still more phenyl)]. EXAMPLE:Methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridine-3- carboxylate. USE:Having angiectasia based on calcium antagonism in combination with platelet aggregation inhibition and useful as an antihypertensive agent, a vasodilator, a medicine for treatment of cerebral circulation and an antithrombotic agent. PREPARATION:For example, a compound [e.g. 4-(3-nitrophenyl)-3-pyridyl-3- buten-2-one] of formula II is reacted with a compound (e.g. ethyl 3- aminocrotonate) of formula III to obtain the objective compound (exemplified compound) of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a form of vasodilatory action and platelet aggregation inhibitory action based on calcium antagonism (in the formula, Ar' and A
r'' are the same or different, substituted or unsubstituted aromatic hydrocarbon or aromatic heterocyclic group, R1 is C0z
R'', SOJ', COR'.

CONRg, CN or N (h represents a hydrogen atom, a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 2 to 10 carbon atoms, and the group is optionally a lower alkyl group, lower alkoxy group, substituted or unsubstituted phenoxy group or thiophenyl group, substituted amine group, substituted or unsubstituted cyclic amino group, substituted or unsubstituted phenyl group, substituted or unsubstituted aromatic heterocyclic group, or trihalomethyl group R3 represents a lower alkyl group, R4 represents a lower alkyl group or phenyl group, and R5 represents a lower alkyl group.

) This relates to a 1,4-dihydropyridine derivative represented by:

[Prior Art] Certain 1,4-dihydropyridine-3,5-dicarboxylate compounds have a vasodilatory effect based on calcium antagonistic action, and have already been used as coronary vasodilators, cerebral circulation improving agents, or antihypertensive agents. Provided for medical purposes.

Representative compounds include, for example, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxylic acid-dimethyl ester (-
Ship name: Nifedipine, U.S. Pat. No. 3,644,627) and 1,4-dihydro-2,6-dimethyl-4-(3-
nitrophenyl)pyridine-3,5-dicarboxylic acid-3
-(2-(N-benzyl-N-methylamino)ethyl]
Examples include ester-5-methyl ester hydrochloride (ship name: nicardipine, Japanese Patent Publication No. 55-45075).

Furthermore, 1,4-dihydropyridine-based compounds are being developed that have vasodilatory effects based on calcium antagonistic effects and platelet aggregation inhibitory effects (for example, JP-A-56
-140989, 60-215684, 61-
No. 10576, No. 61-5076, No. 61-1975
No. 78, No. 60-226876, No. 61-47477
No. 61-212581, No. 61-187468, etc.).

[Problem that the invention seeks to solve]

1,4- represented by nifedipine and nicardipine
Dihydropyridine compounds are based on calcium antagonism (have an excellent vasodilatory effect), but they have not always been satisfactory in the treatment of arteriosclerotic diseases.

Therefore, we are aiming to develop a circulatory system drug that suppresses platelet aggregation, which is a factor in the formation of blood clots, and can be used as a treatment and preventive drug for arteriosclerotic diseases. -Research on dihydropyridine derivatives is currently underway.However, no compound has yet been found that can necessarily satisfy the desired effect.
The development of more effective derivatives is desired.

[Means to solve the problem]

The present inventors aimed to increase the usefulness of 1,4-dihydropyridine derivatives as therapeutic agents for arteriosclerotic diseases, and as a result of intensive research, found that the compound group represented by the formula (1) has a calcium antagonistic effect. They discovered that it has vasodilatory effect and platelet aggregation inhibiting effect, and completed the present invention. That is, the compounds of the present invention are useful as therapeutic and preventive agents for cardiovascular diseases, and are useful as antihypertensive agents, vasodilators, cerebrovascular improvers, and antithrombotic agents. This invention relates to 1,4-dihydropyridine derivatives.

In the 1,4-dihydropyridine derivative represented by the above-mentioned formula (I), Ar' and Ar'' are the same or different, phenyl group, pyridyl group, quinolyl group, isoquinolyl group, furyl group, thienyl group, benzoxane group. An aromatic group or an aromatic heterocyclic group such as a silyl group, a benzthiazolyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidyl group, an indolyl group, a naphthyl group, a benzoxadiazolyl group, a benzthiadiazolyl group, and an acid group. is optionally fluorine, chlorine, bromine, iodine, a halogen atom, a cyan group, a nitro group, a trifluoromethyl group, a trichloromethyl group,
Selected from azide group, amide group, lower alkyl group, lower alkoxy group, benzoyl group, lower alkylthio group, thiophenoxy group, phenoxy group, lower alkoxycarbonyl group, lower acyl group, benzyloxy group, hydroxy group, cinnamyloxy group may have a substituent.

Examples of Ar', Ar'' include phenyl group, 2-nitrophenyl L 3-nitrophenyl L 4-nitrophenyl group, 2-cyanophenyl group, 2-bromophenyl group, 3-bromophenyl!, 4-bromo phenyl group, 2
-Chlorophenyl L3-chlorophenyl L4-chlorophenyl! , 2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2-cyanophenyl group, 3
-cyanophenyl group, 4-cyanophenyl group, 2.3-
Dichlorophenyl group, 2,6-dichlorophenyl group, 3
．． 5-dichlorophenyl group, 2-furyl group, furyl group,
thienyl group, 3-thienyl group, 1-naphthyl group, 2-naphthyl group, 3-azidophenyl group, 2-trifluoromethylphenyl L3-toIJ fluoromethylphenyl group,
4-trifluoromethylphenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group,
2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-benzyloxyphenyl group, 3-benzyloxyphenyl group, 2-cinnamyloxyphenyl group, 3-cinnamyloxyphenyl group, 3- Benzoylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group,
4-Methylthiophene/L4.3-) dichloromethylphenyl group, 2-pyridyl group, pyridyl group, 4-pyridyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group 1-isoquinolyl group, 2- Quinoxalyl group, 2-''rolopyridyl group, 6-chloropyridyl group, 2-methylpyridyl group, 6-methylpyridyl group, 2methoxypyridyl group,
6-methylpyridyl group, 5-bromopyridyl group, 2-aminopyridyl group, 2-mercaptopyridyl group, 3-pyridazinyl group, 4-pyridazinyl group, pyrazinyl group, 2
-pyrimidyl group, 5-pyrimidyl group, 7-benzoxasilyl group, 7-benzthiazolyl group, 3-benzoxadiazolyl group, 3-benzthiadiazolyl group, 2-indolyl group, 3-indolyl group, 5-indolyl group It can indicate a group, etc.

R1 is CO□R” So□R', COR', C0
It is a group represented by NRz, CN or KameNO2.

R2 is a hydrogen atom, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-
-decyl group, isopropyl group, isobutyl group, cyclopentyl group, cyclohexyl group, propenyl group, 2-butenyl L3-butenyl group, 2-pentynyl i, 2.4-hexagenyl group, 2.4-hexacyinyl group, hexa-
A straight chain, branched chain, or cyclic saturated or unsaturated hydrocarbon group such as 4-en-2-yne group, and the acid group may optionally be a methyl group, ethyl group, propyl group, isopropyl group,
lower alkyl groups such as methoxy groups, ethoxy groups, lower alkoxy groups such as propoxy groups, substituted or unsubstituted phenoxy groups, substituted or unsubstituted thiophenyl groups, dimethylamino groups, diethylamino groups, N-benzyl-N-methyl Substituted amino groups such as amine groups, substituted or unsubstituted piperazinyl groups, cyclic amino groups such as piperidinyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted pyridyl groups, quinolyl groups, isoquinolyl groups, furyl groups, thienyl group, an aromatic heterocyclic group such as a benzoxasilyl group, a benzthiazolyl group, a pyridazinyl group, a pyrazinyl group, a pyrimidyl group, an indolyl group, a naphthyl group, a benzoxadiazolyl group, a benzthiadiazolyl group, or a trihalomethyl group. May be replaced. Examples of R2 include hydrogen atom, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, isopropyl group, isobutyl group, cyclopentyl group, cyclohexyl group, allyl group, 2-propyn-1-yl group, (E
)-2-buten-1-yl group, (E)-3-butene-1
-yl group, (E) 2-penten-1-yl group, (2E,
4E) -2,4-hexagenyl group, 2,4-hexacyinyl group, (E) hex-4-en-2-yne group, (
E) -3-phenyl-2-propen-1-yl group, (Z
)-3-phenyl-2-propen-1-yl group, 3-phenyl-2-propyn-1-yl group, (2E, 4E)
-5-phenyl-2,4-pentadien-1-yl group,
5 phenyl-penta-2,4-diyn-1-yl group, (
E)-5-phenyl-pent-2-en-4-yn-1
-yl group, (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propen-1-yl group, (E)-
3-(3-(1-imidazolylmethyl)phenyl)-2
-propen-1-yl L (E') -3-(2-(L
-imidazolylmethyl)phenyl)-2-propene-1
-yl group, (E)-3-(4-(1-imidazolyl)phenyl)-2-propen-1-yl group, (Z)-3-(
4-(1-imidazolylmethyl)phenyl)-2-propen-1-yl group, (E)-3-(6-(1-imidazolylmethyl)pyridin-2-yl)-2-propen-1
-yl group, (E)-3-(5-(1-imidazolylmethyl)furan-2-yl)-2-propen-1-yl group,
(E)-3-(5-(1-imidazolylmethyl)thiophen-2-yl)-2-propen-1-yl group, (E)
-3-phenyl-1-methyl-2-propen-1-yl group, (E)-1-fluoro-3-phenyl-2-propen-1-yl group, 2-methoxyethyl group, 3-methoxypropyl group , 3-ethoxypropyl group, 2-phenoxyethyl group, 2-thiophenoxyethyl group, 2-(N-methylamine)ethyl group, 2 (N,N-dimethylamino)ethyl group, 2-(N-phenyl- N-methylamino)ethyl group, 2-(N,N-diethyl)aminoethyl group, 2-(N-benzyl-N-methyl)aminoethyl group,
2-(1-piperazinyl)ethyl L4-(1-piperazinyl)butyl L6-(1-piperazinyl)hexyl group,
2-(4-piperidinyl)ethyl L2-(4-phenylpiperazin-1-yl)ethyl L3-(4-phenylpiperazin-1-yl)propyl group, 4-(4-phenylpiperazin-1-yl)butyl L6 -(4-phenylpiperazin-1-yl)hexyl group, 2-(4-phenylpiperidin-1-yl)ethyl L3-(4-phenylpiperidin-1-yl)propyl group, 4-(4-phenylpiperidin-1-yl) 1-yl)butyl group, 6-(4-phenylpiveridin-1-yl)hexyl group, 2-(4-(
diphenylmethyl)piperazin-1-yl)ethyl group,
3- (4-(diphenylmethyl)piperazin-1-yl)propyl L4-(4-(diphenylmethyl)piperazin-1-yl)butyl group, 6- (4-(diphenylmethyl)piperazin-1-yl)hexyl group, 2-morpholinoethyl group, N-benzylpyrrolidin-3-yl-
group, N-benzylpiperidin-3-yl-L2-(1,
2,3,4-tetrahydroisoquinolin-2-yl)ethyl group, 2,2.2-)lifluoroethyl group, 2-(
3,7-sihydro-3,7-cymethyl-IH-purine-2,6-sion-1-yl)ethyl group, 2(1,2,3
, 6-tetrahydro-1,3-dimethyl-2<6-thioxo-7H-purin-7-yl)ethyl group, etc.

R3 is a lower alkyl group, and lower means 1 to 3 carbon atoms.
It means a group that represents .

Examples of the lower alkyl group for R3 include methyl, ethyl, n-propyl, and isopropyl.

R4 is a lower alkyl group or a phenyl group, and lower means a group having 1 to 3 carbon atoms.

Examples of the lower alkyl group and phenyl group for R4 include methyl group, ethyl group, n-propyl group, isopropyl group, and phenyl group.

RS is a lower alkyl group, and lower means a group having 1 to 3 carbon atoms. Examples of the lower alkyl group for R5 include methyl group, ethyl group, n-propyl group, isopropyl group. etc. can be shown.

The 1,4-dihydropyridine derivative represented by the above-mentioned format (1) can be produced, for example, by the following production method 1 or 2.

(Production method 1) The 1,4 dihydropyridine derivative represented by the above-format (I) of the present invention is represented by the -format % formula % ([) (wherein Ar' and Ar'' are the same as above). Compounds with the general formula C1rz-C(NHx)=CHR' ・-
-----(II[) (In the formula, R1 is the same as above.)
It is produced by reacting with the compound represented by

The compound represented by the above-format (n) is 4-(2
-nitrophenyl)-3-pyridyl-3-butene-2-
, t, 4-(3-nitrophenyl)-3-pyridyl-3-buten-2-one, 4(4-nitrophenyl)-3
-pyridyl-3-buten-2-one, 4-(2-nitrophenyl)3-(2-pyridyl)-3-buten-2-one, 4-(3-nitrophenyl)-3-(2-pyridyl )-3-buten-2-one, 4-(4-nitrophenyl)-3-(2-pyridyl)-3-buten-2-one, 4
-(2-nitrophenyl)-3(4-pyridyl)-3-
Buten-2-one, 4-(3-nitrophenyl)-3-
(4-pyridyl)-3-buten-2-one, 4-(4-
Nitrophenyl)-3-, (4-pyridyl)-3-buten-2-one, 4-(2-cyanophenyl)-3-pyridyl-3-buten-2-one, 4-(3-cyanophenyl) -3-pyridyl-3-buten-2-one, 4-(4
-cyanophenyl)-3-pyridyl-3-buten-2-one, 4-(2,3-dichlorophenyl)-3-pyridyl-3-buten-2-one, 4-(3,5-dichlorophenyl)-3- Pyridyl-3-buten-2-one, 4-(
2,6-dichlorophenyl)-3-pyridyl-3-buten-2-one, 3-pyridyl-4-(2-trifluoromethylphenyl)-3-buten-2-one, 3-pyridyl-4-(3-) (lifluoromethylphenyl)-3-buten-2-one, 3-pyridyl-4-(4-)lifluoromethylphenyl)-3-buten-2-one, 4-(2
-furyl)-3-pyridyl-3-buten-2-one, 4
-furyl-3-pyridyl-3-buten-2-one, 3~
Viridy-4-thienyl-3-buten-2-one, 3-
Pyridyl-4-(3-thienyl)-3-buten-2-one, 3-pyridyl-4-(2-quinolyl)-3-buten-2-one, 3-pyridyl-4-(3-quinolyl)-3
-Buten-2-one, 3-pyridyl-4-(4-quinolyl)-3-buten-2-one, 4-(2-methoxyphenyl)-3-(2-pyridyl)-3-buten-2-one , 4-(3-methoxyphenyl)-3-(2-pyridyl)-3=buten-2-one, 4-(4-methoxyphenyl)-3-(2-pyridyl)-3-buten-2-one ,
4-(3-nitrophenyl)-3-pyrazinyl-3-buten-2-one, 4-(3-nitrophenyl)-3-
(3-pyridazinyl)-3-buten-2-one, 4-(
3-nitrophenyl)-3-(2-pyrimidyl)-3-
Buten-2-one, 4-(3-nitrophenyl)-3
-(5-pyrimidyl)-3-buten-2-one, 4-(
3-nitrophenyl)-3-(2-quinolyl)-3-buten-2-one, 4-(3-nitrophenyl)-3-(
3-quinolyl)-3-buten-2-one, 4-(3-nitrophenyl)-3,-(4-quinolyl)-3-buten-2-one, 3-(1-isoquinolyl)-4-( 3-nitrophenyl)-3-laten-2-one, 4-(2-pyridyl)-3-pyridyl-3-buten-2-one, 3
, 4-dipyridyl-3-buten-2-one, 4-(4-
pyridyl)-3-pyridyl-3-buten-2-one, 4
-(3-nitrophenyl)-3-(2-quinoxalyl)
-3-buten-2-one, 3-(2-methylpyridyl)
-4-(3-nitrophenyl)3-buten-2-one,
3-(6-methylpyridyl)-4-(3-nitrophenyl)-3-buten-2-one, 3-(2-methoxypyridyl)-4=(3-nitrophenyl)-3-buten-2
-one, 3-(6-methoxypyridyl)-4-(3nitrophenyl)-3-buten-2-one, 3-(5-7'
lomopyridyl)-4-(3-nitrophenyl)-3-buten-2-one, 3-(2-aminopyridyl)-4-(
3-nitrophenyl)-3-buten-2-one, 3-(
2-mercaptopyridyl)-4-(3-nitrophenyl)-3-buten-2-one, 3-(7-benzoxazolyl)-4-(3-nitrophenyl)-3-buten-2
=one, 3-(7-benzthiazolyl)-4-(3-nitrophenyl)-3-buten-2-one, 3-(3-benzoxadiazolyl)-4-(3-nitrophenyl)
-3-buten-2-one, 3-(3-benzthiadiazolyl)-4-(3-nitrophenyl)-3-butene-2
-one, 3-(2-indolyl)-4-(3-nitrophenyl)-3buten-2-one, 3-(3-indolyl)-4-(3-nitrophenyl)-3-buten-2- one, 3-(5-indolyl)-4-(3-nitrophenyl)-3-buten-2-one, 4-(3-nitrophenyl)-3-pyridazinyl-3-buten-2-one, 4-(
3-nitrophenyl)-3-(4-pyridazinyl)-3
-buten-2-one, 4-(3-nitrophenyl)-3
-pyrazinyl-3-buten-2-one, 4-(3-nitrophenyl)-3-quinolyl-3-buten-2-one,
4-(3-nitrophenyl)-3-,(2-quinolyl)
-3-buten-2-one, 4-(3-nitrophenyl)
-3-(4-quinolyl)-3-buten-2-one, 4-
(3-nitrophenyl)-3-(2-quinoxalyl)-
3-buten-2-one, 3-(2-furyl)-4-(
3-nitrophenyl)-3-buten-2-one, 3-(
2-methoxyphenyl)-4-(3-nitrophenyl)
-3-buten-2-one, 3-(2-fluorophenyl)-4-(3-nitrophenyl)-3-buten-2-one, 3-(2-chloropyridyl)-4-(3-nitro phenyl)-3-buten-2-one, 3-(6-chloropyridyl)-4-(3-nitrophenyl)-3-buten-2-one, 3-(2-methoxypyridyl)-4-(3
-nitrophenyl)-3-buten-2-one, 3-(6
-methoxypyridyl)-4-(3-nitrophenyl)-
3-buten-2-one, 3-(2-methylpyridyl)-
4-(3-nitrophenyl)-3-buten-2-one,
3-(1-isoquinolyl)-4-(3nitrophenyl)-3-7'thene-2-, t7.3-(5-isoquinolyl)-4-(3-nitrophenyl)-3-butene-2
-one, 4-(3-nitrophenyl)-3-thienyl-
3-buten-2-one, 4-(1-naphthyl)-3-pyridyl-3-buten-2-one, 4-(2-naphthyl)
-3-pyridyl-3-buten-2-one, 4-(3-azidophenyl)-3-pyridyl-3-buten-2-one,
4-(2-methylphenyl)-3-pyridyl-3-buten-2-one, 4-(3-methylphenyl)-3-pyridyl-3-buten-2-one, 4-(4-methylphenyl)- 3-pyridyl-3-buten-2-one, 4-(
2-chlorophenyl)-3-pyridy-3-butene-2
-one, 4-(2-chlorophenyl)-3-pyridyl-
3-Pten-2-one, 4-(2-chlorophenyl)-
3-pyridyl-3-buten-2-one, 4-(2-bromophenyl)-3-pyridyl-3-buten-2-one,
4-(3-bromophenyl)-3-pyridyl-3-buten-2ione, 4-(4-bromophenyl)-3-pyridyl-3-buten-2-one, 4-(2-iodophenyl)-3 -pyridyl-3-buten-2-one, 4-(3
-iodophenyl)-3-pyridyl-3-butene-2-
on, 4-(4-iodophenyl)-3-pyridyl-3
-buten-2-one, 4-(1-isoquinolyl)-3
-pyridyl-3-buten-2-one, 4-(5-isoquinolyl)-3-pyridyl-3=buten-2-one, 4-
(2-hydroxyphenyl)-3-pyridyl-3-buten-2-one, 4-(3-hydroxyphenyl)-3-
Pyridyl-3-buten-2-one, 4-(4-hydroxyphenyl)-3-pyridyl-3-buten-2-one,
4-(2-benzyloxyphenyl)-3pyridyl-3
-buten-2-one, 4-(3-benzyloxyphenyl)-3-pyridyl-3-laten-2-one, 4-(4
-benzyloxyphenyl)-3-pyridy-3-buten-2-one, 4-(2-cinnamyloxyphenyl)
-3-pyridyl-3-buten-2-one, 4-(3-cinnamyloxyphenyl)-3-pyridyl-3-buten-2-one, 4-(4-cinnamyloxyphenyl)
-3-pyridyl-3-buten-2-one 4-(3-benzoylphenyl)-3-pyridyl-3-buten-2-one and the like can be used.

Further, as the compound represented by the above-mentioned form (III), methyl 3-aminocrotonate, ethyl 3-aminocrotonate, n-propyl 3-aminocrotonate,
n-butyl 3-aminocrotonate, n-pentyl
3-aminocrotonate, n-hexyl 3-aminocrotonate, n-heptyl 3-aminocrotonate, n-octyl 3-aminocrotonate, n-nonyl 3-aminocrotonate, n-decyl 3-aminocrotonate, Isopropyl 3-aminocrotonate,
Isobutyl 3-aminocrotonate, cyclopentyl 3-aminocrotonate, cyclohexyl 3-aminocrotonate, allyl 3-aminocrotonate, 2
-Propyn-1-yl 3-aminocrotonate, (E)
-2-buten-1yl 3-aminocrotonate, (E
)-3-buten-1-yl 3-aminocrotonate,
(E) 2-penten-1-yl 3-aminocrotonate, (2E,4E) -2,4-hexagenyl 3-
Aminocrotonate, 2,4-hexacyinyl 3-aminocrotonate, (E)-hex-4-en-2-
Yin 3-aminocrotonate, (E)-3-phenyl-2-propen-1-yl 3-aminocrotonate,
(Z) -3-phenyl-2-propen-1-yl 3
-Aminocrotonate, 3-phenyl-2-propyne-
1-yl 3-aminocrotonate, (2E, 4B)
-5-phenyl-2,4-pentadien-1-yl 3
-Aminocrotonate, 5-phenyl-penta-2,4
-diyn-1-yl 3-aminocrotonate, (E)
-5-phenyl-pent-2-en-4-yn-1-yl 3-aminocrotonate, (E)-3-(4-(1-
imidazolylmethyl)phenyl)-2-propene-1-
yl 3-aminocrotonate, (E)-3-(3-(
1-imidazolylmethyl)phenyl)2-propene-1
-yl 3-aminocrotonate, (E) -3-(
2-(1-imidazolylmethyl)phenyl)-2-propen-1-yl 3-aminocrotonate, (E)-3
-(4-(1-imidazolyl)phenyl)-2-propen-1-yl 3-aminocrotonate, (Z)-3-(
4-(1-imidazolylmethyl)phenyl)-2-propen-1-yl 3-aminocrotonate, (E)3-
(6-(1-imidazolylmethyl)pyridin-2-yl)-2-propen-1-yl 3-aminocrotonate, (E)-3-(5-(1-imidazolylmethyl)furan-2-yl) -2-propen-1-yl 3-aminocrotonate, (E)-3-(5-(1-imidazolylmethyl)thiophen-2-yl)-2-propene-1
-yl 3-aminocrotonate, (E)-3-phenyl-1-methyl-2-propen-1-yl 3-aminocrotonate, (E)-1-fluoro-3-phenyl-2
-propen-1-yl 3-aminocrotonate, 2-
Methoxyethyl 3-aminocrotonate, 3-methoxypropyl 3-aminocrotonate, 3-ethoxypropyl 3-aminocrotonate, 2-phenoxyethyl 3-aminocrotonate, 2-thiophenoxyethyl 3-aminocrotonate, 2 -(N-methylamino)ethyl 3-aminocrotonate, 2-(N,N-dimethylamino)ethyl 3-aminocrotonate, 2-
(N-phenyl-N-methylamino)ethyl 3-aminocrotonate, 2-(N,N-diethyl)aminoethyl 3-aminocrotonate, 2-(N-benzyl, N-
methyl)aminoethyl 3-aminocrotonate, 2-
(1-Piperazinyl)ethyl 3-aminocrotonate, 4-(1-piperazinyl)butyl 3-aminocrotonate), 6-(1-piperazinyl)hexyl 3-aminocrotonate, 2-(4-piperazinyl)ethyl 3
-aminocrotonate, 2-(4-phenylpiperazin-1-yl)ethyl 3-aminocrotonate, 3-(
4-phenylpiperazin-1-yl)propyl 3-aminocrotonate, 4-(4-phenylpiperazine-1
-yl)butyl 3-aminocrotonate, 6-(4-
Phenylpiperazin-1-yl)hexyl 3-aminocrotonate, 2-(4-phenylpiperidin-1-yl)ethyl 3-aminocrotonate, 3-(4-phenylpiperidin-1-yl)propyl 3-aminocrotonate nate, 4-(4-phenylpiperidin-1-yl)
Butyl 3-aminocrotonate), 6-(4-phenylpiperidin-1-yl)hexyl 3-aminocrotonate, 2-(4-(diphenylmethyl)piperazine-
1-yl)ethyl 3-aminocrotonate, 3-(
4-(diphenylmethyl)piperazin-1-yl)propyl 3-aminocrotonate, 4-(4-(diphenylmethyl)piperazin-1-yl)butyl 3-aminocrotonate, 6-(4-(diphenylmethyl)piperazine) -1-yl)hexyl 3-aminocrotonate, 2
-morpholinoethyl 3-aminocrotonate, N-benzylpyrrolidin-3-yl 3-aminocrotonate, N-benzylpiperidin-3-yl 3-aminocrotonate, 2-(1,2,3,4-tetrahydroisoquinoline -2-yl)ethyl 3-aminocrotonate, 2,2.2-1-lifluoroethyl 3-aminocrotonate, 2-(3,7-sihydro-3,7-dimethyl-IH-purine-2,6-dione) 1-yl)ethyl 3-aminocrotonate, 2-(1,2,3,6-tetrahydro-1,3-dimethyl-2゜6-thioxo-7H-purin-7-yl)ethyl 3-aminocrotonate, 3-aminocrotonitrile, N,N-diethyl 3-amino-
2-butenamide, 3-amino-1-phenyl-2-buten-1-one, 4-amino-3-penten-2-one, 2-amino-1-nitro-1-propene, methyl 3
-amino-2-propenesulfinate, etc. can be used. The reaction is carried out without a solvent or with a solvent inert to the reaction, such as tetrahydrofuran, lI4-dioxane,
It can be carried out in benzene, toluene, methanol, ethanol, propatool, isopropanol, dimethyl sulfoxide, dimethylformacide.

The reaction proceeds smoothly by selecting a temperature in the range of -50 to 150°.

(Production method 2) The 1,4 dihydropyridine derivative represented by the above-format (1) of the present invention is a -formula (wherein Ar' and Ar'' are the same as above, Z is a hydroxyl group or a halogen atom, methanesulfonyloxy group,
Carboxylic acid derivatives represented by active ester residues such as benzotriazole-1-oxy group and succinimide group and the general formula, )10-R"
In the formula, R2 is the same as above. ) can also be produced by reacting with an alcohol derivative represented by.

The carboxylic acid derivative represented by the above-format (IV) is a compound that can be easily obtained by the method shown in the reference example,
Examples of carboxylic acid derivatives (IV) include 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)
-5-pyridylpyridine-3-carboxylic acid chloride,
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(2-pyridyl)pyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-5-pyridylpyridine-3-
Carboxylic acid, 1,4-dihydro-2,6-dimethyl-4
-(3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyrazinylpyridine-3 -carboxylic acid, 1,4-dihydro-2,
6-,') thyl-4-(3-nitrophenyl)-5-(
3-pyridazinyl)pyridine-3-carboxylic acid, 1.4
-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridazinyl)pyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3
-nitrophenyl)-5-(2-pyrimidyl)pyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(5-pyrimidyl)pyridine- 3-carboxylic acid, 1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)5-(
2-quinolyl)pyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(3-quinolyl)pyridine-3-carboxylic acid,
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-quinolyl)pyridine-3-
Carboxylic acid, 1,4-dihydro-2,6-dimethyl-5
-(1-isoquinolyl)-4-(3-nitrophenyl)
Pyridine-3-carboxylic acid, 1,4-dihydro-2,6
-Simethyl-4-(3-nitrophenyl)-5-(2-
quinoxalyl)pyridine-3-carboxylic acid, 1,4dihydro-2,6-dimethyl-5-(2-methylpyridyl)
-4-(3-nitrophenyl)pyridine-3-carboxylic acid, 1,4-dihydro-2,6-cymethyl-5-(6
-methylpyridyl)-4-(3-nitrophenyl)pyridine-3-carboxylic acid, 1゜4-dihydro-2,6-dimethyl-5-'(2-methoxypyridyl)-4-(3-
nitrophenyl)pyridine-3-carboxylic acid, 1,4-
Dihydro-2,6-dimethyl-5-(6-methoxypyridyl)-4-(3-nitrophenyl)pyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-5-
(2-Mercaptopyridyl)-4-(3-nitrophenyl)pyridine-3-carboxylic acid, 5-(5-bromopyridyl)-1,4-dihydro-2,6-simethyl-4-
(3-nitrophenyl)pyridine-3-carboxylic acid, 5
-(2-aminopyridyl)-1゜4-dihydro-2,6
-Simethyl-4-(3-nitrophenyl)pyridine-3
-carboxylic acid, 5-(2-chloropyridyl)-1,4-
Dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid, 5-(6-chloropyridyl)-1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)pyridine-3-carboxylic acid, 4-
(7-benzoxazolyl)-1,4-dihydro-2,
6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(7-benzthiazolyl)-1,4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(3-benzoxadiazo Lil)-1,4
-dihydro-2,6-dimethyl5-pyridylpyridine-
3-carboxylic acid, 4-(3-benzthiadiazolyl)-
1,4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-
Cymethyl-4-(2-indolyl)-5-pyridylpyridine-3-carboxylic acid, ■,4-dihydro2,6-dimethyl-4-(3-indolyl)-5-pyridylpyridine-3-carboxylic acid, 1,4 -dihydro-2,6dimethyl-4-(5-indolyl)-5-pyridylpyridine-
3-carboxylic acid, 4-(2-cyanophenyl)-1,4
-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-5-pyridy-4-(2-)lifluoromethylphenyl)pyridine-3-carboxylic acid, ■, 4-dihydro-2,6-cymethyl-5-pyridyl-4-(3-trifluoromethylphenyl)pyridine-3-carboni7.1
．． 4-dihydro-2,6-cymethyl-5-pyridyl-4
=(4-trifluoromethylphenyl)pyridine-3-
Carboxylic acid, 4-(2-bromophenyl)=1,4-dihydro-2,6-dimethyl-5-pyridylpyridine-3
-carboxylic acid, 4-(3-bromophenyl)-1,4-
dihydro-2,6-cymethyl-5-pyridylpyridine-
3-carboxylic acid, 4-(4-promophenyl)-L4-
Dihydro-2+ 6ymethyl-5-pyridylpyridine-3-carboxylic acid, 4-(2-chlorophenyl)-1
, 4-dihydro-2,6-cymethyl-5-pyridylpyridine-3-carboxylic acid, 4-(3-chlorophenyl)
-L4-dihydro-2,6-cymethyl-5-pyridylpyridine-3-carboxylic acid, 4-(4-chlorophenyl)
-1,4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-
Pyridylpyridine-3-carboxylic acid, 4-(2,6-dichlorophenyl)-L4-dihydro-2,6-cymethyl-5-pyridylpyridine-3-carboxylic acid, 4-(3
,5-dichlorophenyl)-1,4-dihydro-2,6
-Simethyl-5-pyridylpyridine-3-carboxylic acid,
1.4-dihydro-2,6-dimethyl-4-(2-furyl)-5-pyridylpyridine-3-carboxylic acid, 1.4
-dihydro-2,6-dimethyl-4-furyl-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2
, 6-dimethyl-5-pyridyl-4-thienylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-5-pyridyl-4-(3-thienyl)pyridine-3
-carboxylic acid, 4-(3-azidophenyl)-1,4-
dihydro-2,6-cymethyl-5-pyridylpyridine-
3-Carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(1-naphthyl)-5-pyridylpyridine-3-
Carboxylic acid, 1,4-dihydro-2,6-dimethyl-4
-(2-naphthyl)5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-cymethyl-4-(2
-iodophenyl)-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-simethyl-4-(
3-iodophenyl)-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-simethyl-4-
(4-iodophenyl)-5-pyridylpyridine-3
-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-methylphenyl)-5pyridylpyridine-3
-Carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-methylphenyl)-5-pyridylpyridine-
3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(4-methylphenyl)-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4(2- methoxyphenyl)-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-methoxyphenyl)-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro- 2,6-
Dimethyl-4-(4-methoxyphenyl)-5-pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,
6-Simethyl-4-(4-methylthiophenyl)-5-
Pyridylpyridine-3-carboxylic acid, 1,4-dihydro-2,6-dimethyl-4- (2-hydroxyphenyl)-5-pyridylpyridine-3-carboxylic acid, 1,4-
Dihydro-2,6-dimethyl-4-(3-hydroxyphenyl)-5-pyridylpyridine-3-carboxylic acid, 1゜4-dihydro-2,6-dimethyl-4-(4-hydroxyphenyl)-5-pyridylpyridine- 3-carboxylic acid, 4-(2-benzyloxyphenyl)1,4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(3-benzyloxyphenyl)-1,
4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(4-benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(2-cinnamyloxyphenyl")-L4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(
3-cinnamyloxyphenyl)-1,4-dihydro-
2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, 4-(4-cinnamyloxyphenyl)-1,4
-dihydro-2,6-cymethyl-5-pyridylpyridine-3-carboxylic acid, 4-(3-benzoylphenyl)-
L4-dihydro-2,6-dimethyl-5-pyridylpyridine-3-carboxylic acid, etc. can be shown.

Moreover, the alcohol derivative represented by the above-mentioned formula (V) can be produced by deriving from an industrially easily available compound or an industrially easily available raw material.

Examples of alcohol derivatives include methyl alcohol, ethyl alcohol, n-propyl alcohol, n-butyl alcohol, n-pentyl alcohol, n-hexyl alcohol, n-hebutyl alcohol, n-octyl alcohol, n-nonyl alcohol, n- -decyl alcohol, isopropyl alcohol, isobutyl alcohol,
Cyclopentyl alcohol, cyclohexyl alcohol, allyl alcohol, 2-propyn-1-ol, (E
)-2-buten-1-ol, (E)-3-butenol 1
-ol, (E)-2-penten-1-ol, (2E
, 4E) -2,4-hexadien-1-ol, 2,
4-Hexadiyn-1-ol, (E)-hex-4
-eno-2-yn-1-ol, (E)-3-phenyl-2-propen-1-ol, (Z)3-phenyl
-2-propen-1-ol, 3-phenyl-2-propyn-1-ol, (2E,4E)-5-phenyl-
2,4-pentadien-1-ol, 5-phenyl-pent-2,4-diyn-1-ol, (E)-5-phenyl-pent-2-en-4-yn-1-ol, (E)
-3-(4-(1-imidazolylmethyl)phenyl)-
2-propen-1-ol, (E)-3-(3-(1-
imidazolylmethyl)phenyl)-2-propene-1-
ol, (E)-3-(2-(1-imidazolylmethyl)phenyl)-2-propen-1-ol, (E)-3
-(4-(1-imidazolyl)phenyl)-2-propen-1ol, (Z)-3-(4-(1-imidazolylmethyl)phenyl)-2propen-1-ol, (E)
-3-(6-(1 imidazolylmethyl)pyridine-2
-yl)-2-propen-1-ol, (E)-3-(
5-(1-imidazolylmethyl)furan-2-yl)-
2-propen-1-ol, (E)-3-(5-(1-
imidazolylmethyl)thiophen-2-yl)-2-propen-1-ol, (E)-3-phenyl-1-methyl-2-propen-1-ol, (E)1-fluoro-3-phenyl- 2-7'lopen-1ol, 2-methoxyethanol, 3-methoxypropanol, 3-ethoxypropanol, 2-phenoxyethanol, 2-thiophenoxyethanol, 2-(N-methylamino)ethanol, 2-(N,N -dimethylamino)ethanol, 2-(N-phenyl-N-methylamino)ethanol, 2-(N,N-dimethyl)aminoethanol, 2
-(N-benzyl, N-methyl)aminoethanol, 2
- (1-piperazinyl)ethanol, 4(1-piperazinyl)butanol, 6-(1-piperazinyl)hexanol, 2-(4-piperidinyl)ethanol, 2-
(4-phenylpiperazin-1-yl)ethanol, 3
-(4-phenylpiperazin-1-yl)propanol, 4-(4phenylpiperazin-1-yl)phthanol, 6-(4-phenylpiperazin-1-yl)hexanol, 2-(4-phenylpiperazin-1-yl) −il)
Ethanol, 3-(4-phenylpiperidin-1-yl)propertool, 4-(4-phenylpiperidin-1-yl)
yl)butanol, 6-(4-phenylpiperidine-1)
-yl)hexanol, 2-(4-(diphenylmethyl)piperazin-1-yl)ethanol, 3-(4-
(diphenylmethyl)piperazin-1-yl)propatur, 4=(4-(diphenylmethyl)piperazine-1
-yl)phthanol, 6-(4-(diphenylmethyl)piperazin-1-yl)hexanol, 2-morpholinoethanol, N-benzylpyrrolidin-3-yl-1
-ol, N-benzylpiperidin-3-ol, 2-
(1,2,3,4-tetrahydroisoquinoline-2-
yl) ethanol, 2,2,2-trifluoroethanol, 2-(3,7-sihydro3゜7-dimethyl-il)
+-purine-2,6-thion-1-yl) ethanol,
Reactions that can produce 2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-thioxo-78-purin-7-yl)ethanol, etc. are preferably carried out in an inert solvent. .

For example, benzene, toluene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, acetone, etc. can be used. Reaction temperature is 0-12
By selecting the 0°C range, the process will proceed smoothly.

The compounds of form (I) obtained by Production Methods 1 and 2 can be isolated by conventional procedures.

C implementation is '13 people)', 15. q fil ta c=-shi & fQ y: p/J#tyf! 'Cost r-if m
<? 53.

Reference Example 1 4-(3-nitrophenyl)-3-pyridyl-3-buten-2-one 2.76 g (20 mmo
le), 3.066 g of 3-nitrobenzaldehyde (
20 mmole) was dissolved in benzene, 0.29 g (20 mmole) of piperidine acetate was added, and the mixture was dehydrated under heating under reflux for 6 hours. After washing with water, drying over anhydrous sodium sulfate, distilling off benzene under reduced pressure, and purifying with silica gel column chromatography, 4.5 g of the title compound (
A yield of 87.9%) was obtained.

NMR (δ, CDCl!, z) 2.47 (311,
s) 7.30 (IH, d, J = 8.4Hz) 7.38 (
IH, M, J = 8.4Hz) 7.39 (LH, dd, J
=7.8Hz, 5Hz) 7.56(LH, dt, J=7
．． 8Hz, 2Hz) 7.78 (1) I, s) 7.92 (LH, s) 8.10 (LH, d, J = 8.4Hz) 8.35 (IH
, d, J=2Hz) 8.66 (IH, dd, J=5flz, 2Hz) Reference Example 2 4-(3-nitrophenyl)-3-(4-pyridyl)-
3-Buten-2-one 1-(4-pyridyl)-2-propanone 4.62 g (
34 mmol), 3-nitrobenzaldehyde 5,1
Dissolve 4 g (34 mmol) in benzene, add 0.49 g (3.4 mmol) of piperidine acetate, and dehydrate while heating under reflux for 3 hours. After washing with water, drying with anhydrous sodium sulfate, distilling off benzene under reduced pressure, purifying with silica gel column chromatography, and recrystallizing from toluene to obtain 7.965 g of the title compound (yield: 87.3
%) was obtained.

NMR (δ, CDCl!, s) 2.45 (31Ls
)7.15(2H,d,J=5.4Hz)7.26(I
H, d, J = 8.4 Hz) 7.37 (IH, t, J = 8
．． 411z) 7.75 (IH, s) 8.01 (IH, s) 8.12 (IH, d, J = 8.4Hz) 8.69 (LH
, d, J=5.4Hz) Reference Example 3 2-cyanoethyl 1,4-dihydro-2,6-di) f
Lu-4-(3-nitrophenyl)-5-hyIJ Zylpyridine-3-carboxylate CH3HCH3 4-(3-nitrophenyl)-3-biIl; Lu-3-buten-2-one 5.365 g (20 mmol), 2
-cyanoethyl 3-aminocrotonate 15.417
g (100 mmol), zinc chloride 5.451 g (
40 mmol), 10 g of molecular sieve 4A,
The mixture is heated under reflux for 5 hours in an inert gas atmosphere using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the title compound was purified by silica gel column chromatography (7.04 g, yield 87%) to obtain the following.

I R (cm-', KBr) NMR (δ, CDCj!l) Reference example 4 2-cyanoethylcyco1696 cyN0.1530,1352νC
N2256 1.86 (3tLs) 2.42 (3H, s) 2, 58-2.66 (2H, m) 4.18-4.30 (2!l, m) 4.78 (1) 1. s) 5.92 (IH, s) 7.19 (LH, dd, J=7.511z, 4.8Hz
)7.26-7.33(1!I,m) 7.37(IH,t,J-7,8Hz)7.49(18
, d, J=7.8Hz) 8.02 (IH, d, J=7.
8Hz) 8.07 (Ill, s) 8.19 (IH, d, J=2Hz) 8.43 (IH, dd, J=4.) IZ, H7
) 1,4-dihydro-2,6-cymethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate C1,HCH3 4-(3-nitrophenyl)-3-(4-pyridyl)-
3-buten-2-one 5.365 g (20 mmol
), 2-cyanoethyl 3-aminocrotonate 9.2
50g (60mmol), zinc chloride 5.451g
(40 mmol) and 10 g of molecular sieve 4A were heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform.

After distilling off the solvent, it was purified by silica gel column chromatography and recrystallized from methanol to obtain the title compound 4.9.
80 g (62% yield) was obtained.

I R (cm-', KBr) v co1704
v 5oz1528,1352νCN2CN2 256Nδ, CD(/!t) 1.97(3H,s)
2.43 (3H, s) 2.60-2.70 (28, m) 4.20-4.33 (211, m) 4.88 (1B, s) 5.78 (ltl, s) 6. 98 (2H, d, J = 6Hz) 7.37 (IH, t, J = 8.4Hz) 7.48 (IH
, d, J=8.411z) 8.03(IH, d, J=
8.411z) 8.08 (ltl, s) 8.13 (2H, d, J=6Hz) Reference example 5 1.4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridyl Pyridine-3-carboxylic acid CH38C11z Sodium methoxide 5.40 g (100 mmol
) was dissolved in anhydrous methanol 40, and 2-cyanoethyl 1,4-dihydro-2,6-simethyl-4-(
4.04 g (10 ports o1) of 3-nitrophenyl)-5-pyridylpyridine-3-carboxylate are added. 5
After stirring for an hour, neutralize with acetic acid and add 400% of water.

The precipitated crystals were collected, washed with water, and then dried under reduced pressure to obtain 2.45 g' (yield: 70%) of the title compound.

FAB Mass 352 (M+1)
NMR (δ, (CD3) zcO) 1.92 (3H, s) 2.38 (3H, s) 4.90 (IH, s) 7.24 (Ill, dd, J = 8Hz, 5Hz) 7.4
6 (IH, d, J=8Hz) 7.50 (IH, t, J=8H2) 7.66 (18
, d, J=8Hz) 7.76 (18, s) 8.01 (IH, d, J=8Hz) 8.09 (IH
,s) 8.25 (IH,s) 8.36 (18,d, J=5Hz) Reference example 6 1.4-dihydro-2,6-cymethyl-4-(3nitrophenyl)-5-(4-pyridyl ) Pyridine-3-carboxylic acid C)13 I C)lz Sodium methoxide 1.35 g (25 mmol)
was dissolved in anhydrous methanol 20%, and 2-cyanoethyl 1,4-dihydro-2,6-dimethyl-4-(3
-nitrophenyl)-5-(4-pyridyl)pyridine-
Add 2.02 g (5 mmol) of 3-carboxylate. After stirring at room temperature for 1 hour, the mixture was neutralized with acetic acid and 400% of water was added. The precipitated crystals were collected, washed with water, and then dried under reduced pressure to obtain 1.71 g (yield: 98%) of the title compound.

FAB Mass 352 (M+1)N
MR (δ, (CD3) zcO) 2.03 (38, s) 2.37 (3H, s) 4.99 (IH, s) 7.09 (2H, d, J=6Hz) 7.50 (IH ,t, J=7H2) 7.67(IE
I, d, J=7Hz) 7.83 (IH, s) 8.02 (IH, d, J=7Hz) 8, 11 (IH, s) 8, 42 (2) 1. d, J=611z) Example 1 Methyl 1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)-5-pyridylpyridine 3-carboxylate ■ 4-(3-nitrophenyl)-3-hisodyl-3-buten-2-one 268 mg (1 mmole), ethyl 3-aminocrotonate 646 mg (5 mmole)
, 273 mg (2 mmole) of zinc chloride, and 500 mm of molecular sieve were heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain 259 mg of the title compound (
A yield of 71% was obtained.

Melting point: 148.5-150.6°C
I R(c+r', KBr); v Co 170
0shi No, 1530.1345 Mass spectrometry; Molecular formula CzoH + JzOa Theoretical value 365.13750 Actual value 365.1375 NMR (δ, CDCl,); 1.87 (3tl, s),
2.40 (3H, s).

3.62 (3H, s), 4.79 (LH, s), 5
．． 60 (18,s).

7.16 (IH, dd, J=8) 1z, 511z),
7.26 (LH, dt, J=8Hz, 2Hz), 7.
34 (LH, t, J-811z), 7.46 (IH,
d, J=8hz), 8.01. (Ill, ddd, J
=8Hz.

2Hz, IHz), 8.06 (IH, t, J=2Hz
), 8.22 (1B, d, J=2Hz), 8.42
(IH, dd, J=51 (z, 2Hz) Example 2 Ethyl 1,4-dihydro-2,6-simethyl-4-(
3-nitrophenyl) 3-carboxylate 5-pyridylpyridine 4-(3-nitrophenyl)-3-pyridyl-3-buten-2-one 268 mg (1 mmole), ethyl
3-aminocrotonate 646 (5 mmole), zinc chloride 273 mg (2 mmole), and molecular sieve 4A 500 mm are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature;
Neutralize with saturated aqueous sodium hydrogen carbonate solution and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain 250 μg of the title compound (yield: 6
7%).

Melting point; 01I I R (cl', KBr); J/Co 169
5S NOx 1530.1350 Mass spectrometry; molecular formula Cz+Hz+Ni04 theoretical value 379.
15316 Actual value 379.15322 NMR (δ, CDCf5); 1.19 (38, t, J
=6Hz), 1.88(3H,s), 2.40(3
H, s), 4.0-4.15 (28゜), 4.7
8 (18, s), 5.60 (IH, s), 7.20
(1)1. dd, J=7.511z), 7.29(1
0, d, J = 7Hz).

7.35 (IH, t, J=8Hz), 7.50 (IH
, d, J=8Hz).

8.01 (LH, d, J=8Hz), 8.08 (LH
, s), 8.24 (III, s), 8.43 (Il
l, d, J=5Hz) Example 3 Isopropyl 1,4-dihydro-2,6-dimethyl-4
-(3-nitrophenyl)-5-pyridylpyridine-3
-Carboxylate■ 4-(3-nitrophenyl)-3-pyridyl-3-puten-2-one 268 mg (1 mmole), isopropyl 3-aminocrotonate 715 mg (5 mmole)
273 mmole (2 mmole) of zinc chloride, and 500 mm of molecular sieve 4A were heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. After cooling to room temperature and distilling off saturated aqueous sodium hydrogen carbonate, silica gel column chromatography was obtained.

Melting point: 140.1-141.3°CI
R (cm-', KBr); v CO1705 No., 1530.1350 Mass spectrometry; molecular formula C2□HzNsOa theoretical value 393.
16882 Actual value 393.16837 NMR (δ, CDCfz); ・1.06 (3H, d, J
= 6Hz), 1.23 (3H, d, J = 6Hz),
1.88 (3H, s), 2.40 (311, s).

4.77 (1B, s), 4.95 (Ill, m), 5
．． 57 (IH, s).

7.20-7.41 (3H, m), 7.50 (l) I
, d, J=8Hz).

8.02 (LH, d, J=8Hz), 8.07 (18
,s), 8.27(ill,s), 8.44(IH
, d, J=5Hz) Example 4 n-hexyl 1,4-dihydro-2,6-dimethyl-4
-(3-nitrophenyl)-5-pyridylpyridine-3
-Carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 mmole, hexyl alcohol 1
02mg (1mmole), dicyclohexylcarbodiimide 309■ (1,5mmole), 4-N
, N-dimethylaminopyridine 134 mg (1,1
mmole) in 10 mff1 of toluene while hot,
Heat to reflux for 1 hour. After cooling to room temperature, 20 m2 of chloroform is added. After washing with water, drying over anhydrous sodium sulfate, distilling off the solvent, and purifying by silica gel column chromatography, the title compound was 389.
5%).

Melting point, 120.5-121.6°CI
R(cl', KBr); v Co 1705SNOt 1525.1350 Mass spectrometry; Molecular formula CzsHgJsO4 Theoretical direct 435.21575 Actual value 435.2168O NMR (δ, CDCI!, 3); 0.848 (3
11,t+J=6)1z).

1.12-1.30 (6FI, m), 1.50-1.
60 (2H, m).

1.85(311,sL 2,41(3H,s), 3
．． 96 (18, dt.

J=11.7Hz), 4.04(ltl, dt, J=
11.7Hz).

4.77 (ILs), 5.57 (IH,s), 7.
18 (IH, dd.

J=8.5Hz), 7.28(LH,d, J=8Hz
), 7.34 (IH.

t, J=8Hz), 7.46(IH, d, J=8Hz)
), 8.00 (IH.

d, J=8Hz), 8.05 (IH, s), 8.2
3 (IH, s).

8.43 (LH, d, J=5Hz) Example 5 Cyclohexyl 1,4-dihydro-2+ 6';
Mef Ru 4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350■ (1 mmole), cyclohexanol 10
0■ (1 mmole), dicyclohexylcarbodiimide 309 mg (1.5 mmof), 4 N,
N-dimethylaminopyridine 134 mg (1,1 m
mol was dissolved in 10 ml of toluene while hot, and heated under reflux for 1 hour. After cooling to room temperature, add 20 m of chloroform.
Add 2. After washing with water, it was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 362 tng (yield: 83%) of the title compound.

Melting point; oil J R (cm-', KBr); v Co 169
4S NOx 1532.1350 Mass spectrometry; Molecular formula CzsHzJxOa Theoretical value 433.20011 Actual value 433.19727 NMR (δ, CDCjl!z); 1.10-2.24
(10H, m), 1.87 (3H, s), 2.4H
311, s), 4.64-4.76 (LH.

m), 4.78 (IH, s), 5.58 (1) 1.
s), 7.23 (IH, dd, J=7.7Hz, 4.
9Hz), 7.34(1,H,d.

J=7.7Hz), 7.35(IH,t, J=8.7
Hz), 7.49 (IH, d, J=8.7Hz),
8.01 (IH, d, , J = 8.7Hz).

8.06 (18, s), 8.25 (IH, d, J=1
．． 5Hz).

8.44 (ill, dd, J=4.9Hz, 1
．． 5Hz) Example 6 2-Methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate ■ 1,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)-5-pyridylpyri, 350 μ (1 mmole) of gin-3-carboxylic acid, 76 μ (1 mmole) of 2-methoxyethanol, 309 μ (1,5 mmole) of dicyclohexylcarbodiimide, 4-N , N
-dimethylaminopyridine 134 mg (1,1 mmo
le) in 10 mj2 of toluene while hot, and heated under reflux for 1 hour. After cooling to room temperature, chloroform 20
Add m1. After washing with water, dry with anhydrous sodium sulfate,
After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 348 mg (yield: 85%) of the title compound.

Melting point: 163.0-164.2°CI
R (cm-', KBr); v CO1690SN0.1534.1352 Mass spectrometry; Molecular formula CzJz3NzOs Theoretical value 409.16373 Actual value 409.1656O NMR (δ, CDCj!3); 1.89 (3H, s)
, 2.40 (311, s).

3.32(3)1. s), 3.45-3.58 (28
, m), 4.08-4.25 (2H, m), 4.8
1 (LH, s), 5.65 (IH, s), 7.28
(IH, dd, J=7.8Hz, 3.311z).

7.36 (IH, t, J=7.8Hz), 7.41
(IH, d, J=7.8Hz), 7.54(1)1.
d, J=7.8Hz), 8.02 (LH.

d, J=7.8H,z), 8.08(IH,s),
8.25 (18,s).

8.44 (LH, d, J = 3.3 Hz) Example 7 2-phenoxyethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxy Rate ■ 1.4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridyl and lysine-3-carboxylic acid 35011g (1mmole), 2-phenoxyethanol 138mg (1mmole), dicyclohexylcarbodiimide 309111g (1.5 mmol
e) ,4-N,N-dimethylaminopyridine 134m
g (1.1 mmole) is dissolved hot in 10 m2 of toluene and heated under reflux for 1 hour. After cooling to room temperature,
Add 20 mj2 of chloroform. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying by silica gel column chromatography, the title compound 445 (
A yield of 94%) was obtained.

Melting point; 69.5-70.8°CIR
(cm-', KBr); v CO1696J/
Noz1528.1350 Mass spectrometry; Molecular formula CzJzsNiOs Theoretical value 471.17938 Actual value 471.17893 NMR (δ, CDCj2+); 1.91 (3H, s)
, 2.41 (38, s).

4.02-4.17 (2H, m), 4.29-4.5
0 (2H, m).

4.80 (IH,s), 5.702 (IH9s)+
6.84 (2H.

d, J = 7.8) 1z), 6.96 (IH, t, J
=7.8Hz).

7.20(1)1. t, J=8.2Hz), 7
．． 27 (2H, t, J = 7.8Hz), 7.36 (IH
, dd, J=7.5Hz, 5Hz).

7.43-7.51 (2H, m), 7.96 (IH
, d, J=8.2Hz).

8.07 (18, s), 8.27 (LH, d, J=
2.4t(z), 8.45(18,dd, J=5H
z, 2.4Hz) Example 8 2-(phenylthio)ethyl 1,4-dihydro-2゜6
-Simethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carpoxylate 1,4-dihydro-2,6-simethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carvone Acid 350mg (1mmof), 2 (phenylthio)ethanol 154mg (1mmof), dicyclohexylcarbodiimide 309mm (1.5mmof)
,4-N,N-dimethylaminopyridine 134 tng
c 1.1mmof), toluene 10m! ! , and heated under reflux for 1 hour. After cooling to room temperature,
Add 20 ml of chloroform. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography to obtain 470 mg of the title compound (
A yield of 96% was obtained.

Melting point; oil"c IR (cm-', KBr); v CO1
704ν NO□ 1528.1348 Mass spectrometry; molecular formula CzJz5NsOaS theoretical value 487.
15653 Actual value 487.15736 NMR (δ, CD (f!z); 1.89 (3) 1.s
L 2.40 (3H, s).

3.70 (2H, t, J=7.2Hz), 4.13-
4.27 (2H.

m), 4.78 (LH,s), 5.69 (LHl
s) + 7.14-7.39 (7H, m), 7.42
(IH, d, J=8.4Hz).

7.49 (18, d, J = 7.2Hz), 8.02
(LH, d, J=7.2H2), 8.06 (18,s
), 8.26 (IH, d, J=2.411z), 8
．． 46 (IH, dd, J=6Hz, 2.4Hz) Example 9 2.2.2-1-Lifluoroethyl 1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)-5-
Pyridylpyridine-3-carpoxylate ■ 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 mg (1 mmole), 2,2.2- ) Refluoroethanol 100 mmole (1 mmole), dicyclohexylcarbodiimide 309 mg (1.5 mmole)
mole), 4-N,N-dimethylaminopyridine 13
4■ (1.1 mmole) toluene 10rr+/!
Dissolve while hot and heat under reflux for 1 hour. After cooling to room temperature, 20 m/2 of chloroform is added. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography, the title compound 45
0■ (yield 100%) was obtained.

Melting point: 152.7-154.3°CI
R (cm-', KBr); v CO1710SN021528.1352 Mass spectrometry; Molecular formula C2IH1llF3N304 Theoretical value 4
33.12489 Actual value 433.12338 NMR (δ, CDCf5); 1.8B (3H, s),
2.42 (3H, s).

4.27-4.50 (2H, m), 4.76 (II (
, s), 5.84 (IH, s), 7.26 (LH,
dd, J=6.6Hz, 4.21! z).

7.33 (LH, d, J = 6.6Hz), 7.35 (
IH, t, J = 7.8 Hz), 7.43 (18, d,
J=7.8tlz), 8.03(IH.

d, J=7.8Hz), 8.07(IH,s), 8
．． 23 (IH, s).

8.45 (IH, d, J = 4.2 Hz) Example 10 Allyl 1,4-dihydro-2,6-simethyl-4(3
-nitrophenyl)-5-pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 35 Qmg (1 mmole), allyl Alcohol 58 mg (1 mmole), dicyclohexylcarbodiimide 309 mg (1,5 mmole), 4-
N,N-dimethylaminopyridine 134mg (1,
1 mmole) in 10 m2 of toluene while hot, 1
Heat to reflux for an hour. After cooling to room temperature, 20 mf of chloroform is added. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography to obtain 400 mg of the title compound (yield: 100 mg).
%) was obtained.

Melting point: 141.8-143.6°CI
R (cm, KBr); v CO1695 No.
, 1535.1350 Mass spectrometry; Molecular formula C2□H2IN304 Theoretical value 391.
15316 Actual value 391.15218 NMR (δ, CDCj!i); 1.87 (38, s)
, 2.41 (3H, s).

4.50 (18, dd, J=12.611z),
4.56 (IH, dd, J=12.6)1z), 4
．． 80 (LH, s), 5.14 (IH, d, J=11
Hz), 5.16 (IH, d, J=1'9Hz),
5.63 (18,s).

5.85 (IH, dat, J=19.11.6Hz),
7.16 (IH.

dd, J=8.5Hz), 7.25(LH, d, J=
811z), 7.34 (LH, t, J=8Hz),
7.48 (LH, d, J=8Hz), 8.01 (11
(, d, J=81(z), 8.07(1)1.s),
8.22 (LH.

s), 8.42 (LH, d, J=5Hz) Example 1
1 2-Propyn-1-yl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate 1,4-dihydro-2,
6-Simethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 μ (1 ml Ilo
le), 2-propyn-1-ol 56 mg (1
mmole), dicyclohexylcarbodiimide 30
9.9 mmol (1.5 mmole) and 134 mmole (1.1 mmole) of 4-N,N-dimethylaminopyridine were dissolved in 10 ml of toluene while heating and refluxed for 1 hour. After cooling to room temperature, 20 molar of chloroform is added. After washing with water, the residue was dried over anhydrous sodium sulfate, and the solvent was distilled off, followed by silica gel column chromatography to obtain 410 mg (yield: 100%) of the title compound.

Melting point: 179.2-180.1°CI
R (cm-', KBr); v Co 1695
ν Noz 1530. 1350 Mass spectrometry; Molecule 202□H19N304 Theoretical value 389.
13751 Actual value 389.13593 NMR (δ, CDC1, s); 1.87 (3H, s)
, 2.39 (IH, t.

J=2Hz), 2.41(3H,s), 4.58(
IH, dd, J=15°2Hz), 4.65 (IHl
dd, J=15+2Hz), 4.79 (18°s),
5.68 (IH, s), 7.15 (1) 1. dd, J
=8.511z).

7.25 (IH, dt, J=8.2Hz), 7.35
(LH, t, J = 8Hz), 7.52 (LH, d, J
=8Hz), 8.01(IH, d, J=8Hz),
8.08 (LH, s), 8.22 (18, s),
8.42(1)1. dd, J=5.2Hz) Example 12 (2B,4E)-2,4-hexadien-1-yl 1,
4-dihydro-2,6-dimethyl-4-(3-di)lophenyl)-5-pyridylpyridine-3-carboxylate monobuten-2-one 268 mmole (1 mmole), (2
E+4E) -2,4-hexadien-1-yl 3-
Aminocrotonate 905mg (5mmole),
273 mg (2 mmole) of zinc chloride and 48,500 μm of molecular sieve are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 182 (yield: 42.3%).

Melting point, 162.3-164.2°CI
R(cl'KBr); v CO1695SN
O□1525.1350 Mass spectrometry; molecular formula CzsHzsN30n theoretical value 431.
18446 Actual value 431.18439 NMR (δ, CDC1!, z)i 1.74 (3tl,
d, J=7)1z), 1.87(3H,s), 2.3
9 (3H, s), 4.47 (IH, dd, J=12.
78Z), 4.56 (IH, dd, J=12.7Hz
), 4.79 (IH9s) + 5.55 (IH, dt
, J=13.7Hz), 5.564-(3-nitrophenyl)-3-pyridyl-3(LH,s), 5.6
7 (IH, dq, J=14.7Hz), 6.00 (
18, dd, J-14, 10Hz), 6.11 (I
H, dd, J=13°10Hz), 7.20(LH
, dd, J=8.5Hz), 7.28<LH.

dt, J=5.2Hz), 7.34(IH,t,J
=8Hz), 7.48(IH, d, J=8Hz),
8.00 (LH, d, J=8Hz), 8.06 (
IH, s), 8.23 (IH, d, J=2Hz),
8.42 (IH, dd.

J・5.2Hz) Example 13 (E)-3-phenyl-2-propen-1-yl 1.4
-dihydro-2,6-cymethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate 4-(3-nitrophenyl)-3-pyridyl-3-buten-2-one 268 ■ (1 mmole) , (E)-3
-Phenyl-2-propen-1-yl 3-aminocrotonate 1.08 g (5 mmole), zinc chloride 273 mm (2 mmole), molecular sieve 4A5
00 mg is heated under reflux for 5 hours in 1,4-dioxane as a solvent in an inert gas. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain 315 mg of the title compound (yield 66.
9%).

Melting point, 146.0-147.1°CI
R (cm-', KBr); v Co 1700
CNoz 1530.1350 Mass spectrometry: Molecular formula CzsthsN:+O.

Theoretical value 467.18446 Actual value 467, 18283 NMR (δ, CD0f!, s); 1.88 (3H,
s), 2.42 (3H, s).

4.64 (LH, dd, J=12.7Hz), 4.
72 (IH, dd.

J=12,782), 4.82(LH,S),
5.65 (IH, S).

6.20 (IH, dt, J=15.6Hz), 6.
52 (IH, d, J = 15Hz), 7.24 (18
, dd, J=8.5Hz), 7.26~7.35(
7H, m), 7.48 (IH, d, J=8Hz),
7.99 (IH, d, J = 8Hz), 8.08 (L
H,s), 8.24 (LH.

s), 8.42 (18, d, J=5Hz) Example 1
4 (Z)-3-phenyl-2-propen-1-yl 1.4
-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenylcin-5-pyridylpyridine -3-carboxylic acid 3501 Hg (1 mmole), (Z)-3-phinyl-2-propen-1-ol 135 ■ (1 mmol)
e), 309 g of dicyclohexylcarbodiimide (1
,5 mmole), 4 N+N-dimethylaminopyridine (134 mmole), toluene (10 mmole)
m! Dissolve while hot and heat under reflux for 1 hour. After cooling to room temperature, 20 m2 of chloroform is added.

After washing with water, drying with anhydrous sodium sulfate and distilling off the solvent,
Purification was performed by silica gel column chromatography to obtain 467 mg (yield 100%) of the title compound.

Melting point: 129.9-130.6°CT
R (cm-', KBr); v Co 1698
CNOz 1530.1348 Mass spectrometry; molecular formula CzslhsN304 theoretical value 467,
18446 Actual value 467, 18401 NMR (δ, CDCl!, ); 1.90 (3H, s
), 2.42(3f(,s).

4.73-4.88 (2H, t+), 4.79 (ILs
), 5.70 (IH, s), 5.73 (IH, dt
, J=12Hz, 6)1z).

6.62(1)1. d, J=1211z), 7.15
(2'H, d, J=4Hz).

7.23-7.41 (5H, m), 7.46-7.5
4 (2H, m).

8.01 (IH, d, J=8Hz), 8.06 (11
(,s), 8.28(18,s), 8.46(II
I, d, J = 4.6 Hz) Example 15 3-phenyl-2-propyn-1-yl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) 5-pyridylpyridine-3- Carboxylate 4-(3-nitrophenyl)-3-pyridyl-3-buten-2-one 0.268 g (1 mmole), 3
-Phenyl-2-propyn-1-yl 1.075 g (5 mmole) of 3-aminocrotonate, 0.273 g (2 mmole) of zinc chloride, 0.5 g of molecular sieve 4A, and 1,4-dioxane as a solvent in inert gas. Heat to reflux for 5 hours. Cool to room temperature;
Neutralize with saturated aqueous sodium hydrogen carbonate solution and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 0.33 g (yield: 70.9%) of the title compound.

Melting point: 156°C (decomposed) IR (cm-formula, KBr): v CO1700 NO11530
, 1350 Mass spectrometry; Molecular formula CzJtJ:+Oa Theoretical value 465.16881 Actual value 465.17159 NMR (δ, (:DCj'+); 1.89 (3H, s
), 2.43 (3H, s).

4.82 (IH, d, J=15Hz), 4.84 (I
H,s).

4.99(1)1. d, J=15Hz), 5.68(
III, s).

7.20-7.42 (9H, m), 7.54 (IH,
d, J=811z).

8.00 (LH, d, J=8Hz), 8.11 (it
(,s), 8.26(11(,s), 8.43(I
H, d, J = 5) 1z) Example 16 (2E) -5-phenyl-2-penten-4-yn-
1-yl1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)-5-pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridyl and lysine-3-carboxylic acid 350 mg (1 mmole ), (2E)-5-phinyl-2-penten-4-yn-1-ol 158 m
g (1 mmole), dicyclohexylcarbodiimide 309 mg (1,5 mmole), 4-N, N
-dimethylaminopyridine 134■ (1,1mm61e
) in 10 ml of toluene while hot, and heated under reflux for 1 hour. After cooling to room temperature, 20 m2 of chloroform is added. After washing with water, the residue was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound 475 (yield: 97%).

Melting point: 189.9-191.1°CI
R (cm-', Br); v CO167BνN0
．． 1528.1350 Mass spectrometry; Molecular formula C1゜1hJ304 Theoretical value 491.18446 Actual value 491.18594 NMR (δ, CDCj'+); 1.91 (38, s)
, 2.43 (3H, s).

4.58<IH, dd, J=15Hz5.411z),
4.65 (18゜dd, J=15H2,5,4H2
), 4.82 (IH,S), 5.72 (IHls)
+ 5.80 (ill, d, J=15hz), 6.1
8 (LH.

dt, J=15hz, 5.4Hz), 7.28~7.
53 (9H, m).

8.03 (IH, d, J=8Hz), 8.08 (IH
, s), 8.28 (18, d, J=2.1Hz),
8.46 (18, dd, J=5.7Hz.

2.1Hz) Example 17 (2E,4E)-5-phenyl-2,4-pentadien-1-yl 1,4-dihydro-2,6-simethyl-4=
(3-ditrophenyl)-5-pyridylpyridine-3
-Carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 mg (1 mmole), (2E, 4E)
5-phenyl-2,4-pentadien-1-ol 16
0■ (l mmole), dicyclohexylcarbodiimide 309 mg (1,5 mmole), 4-N,
N-dimethylaminopyridine 134■ (1.1 mmol
Dissolve e) in 10 m2 of toluene while heating and reflux for 1 hour.

After cooling to room temperature, 20 ml of chloroform is added. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography.
The title compound 377■ (yield 76%) was obtained.

Melting point R 1182°C (decomposition) (C11-', KBr); v Co 169
8ν Not 1528.1346 Mass spectrometry; Molecular formula C1゜I (z'rN304 theoretical value 49
3.20011 Actual value 493.19698 NMR (δ, CDCj'+); 1.89 (3H, s
), 2.42 (3H, s).

4.56 (IH, dd, J=14.3Hz, 6.6Hz
), 4.66 (IH, dd, J=14.3Hz, 6
．． 6Hz), 4.82 (IH, s).

5.65 (18, s), 5.80 (IH, dt, J
=15Hz, 6Hz).

6.29 (LH, dd, J=15Hz, 10.2Hz)
, 6.49 (18°dd, J=15.5Hz, 10.
2Hz), 6.72 (IH, d, J=15.58Z)
, 7.18-7.43 (8B, m), 7.50 (L
H.

d, J=8.3Hz), 8.02(IH, d, J=8
．． 3Hz), 8.09(IH,s), 8.26(L
Hld, J=2.4)1z)+8.44(LH.

dd, J=4.8Hz, 2.4flz) Example 18 (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propen-1-yl 1,4-dihydro-2,
6-Simethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carpoxylethoH 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 mg (1 mmole), (E)-3-(4-
(1-imidazolylmethyl)phenyl)-2-propen-1-ol 214 mmole (1 mmole), dicyclohexylcarbodiimide 309 mmole (1,5 mmole)
, 4-NUN-dimethylaminopyridine 134 mg
(1.1 mmole) was dissolved hot in 10 ml of toluene and heated under reflux for 1 hour. After cooling to room temperature, 20 rne of chloroform is added. After washing with water, the residue was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound 530.mu. (yield: 97%).

Melting point; oil IR (am-', KBr); ! /Co
1692ν N0□ 1528.1350 Mass spectrometry; Molecular formula〇3□H29NS04 Theoretical value 547.
22190 Actual value 547.2213 NMR (δ, CDC1,,); 1.86 (3) 1. s
), 2.43 (3tl, s).

4.61 (LH, dd, J=12.6Hz, 6Hz),
4.74(1)1゜dd, J=12.6Hz, 6Hz
), 4.81 (IH, s), 5.19 (2H, s)
, 5.63 (IH, s), 6.20 (IH, dt,
J=16.2Hz, 6.3Hz), 6.47(IH,
d, J=16.2Hz).

6.98 (IH, s), 7.32-7.36 (88,
m), 7.50 (LH, d, J=7.8Hz), 7
．． 97 (IH, d, J=7.8Hz).

8.05 (2H, s), 8.22 (IH, d, J=2
．． 1Hz), 8.41 (IH, dd, J=5.1Hz
, 2.1 Hz) Example 19 (Z)-3-(4-(1-imidazolylmethyl)phenyl)-2-propen-1-yl 114-dihydro-2+
6'; Methyl-4- (3-nitrophenyl)-
5-Pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 210111g (0.6mmole), (Z)-3 −
(4-(1-imidazolylmethyl)phenyl)=2-propen-1-ol 107 ■ (0.5 mmole),
Dicyclohexylcarbodiimide 155■ (0.75m
mole), 4-N,N-dimethylaminopyridine 6
7 (0.55 mmole) was dissolved in 10 ml of toluene while hot, and heated under reflux for 1 hour. After cooling to room temperature, add 20 mj of chloroform! Add.

After washing with water, drying with anhydrous sodium sulfate and distilling off the solvent,
Purified by silica gel column chromatography,
273 mg (yield 100%) of the title compound was obtained.

Melting point; oil IR (am-', KBr); v CO1692
SiN (h 1532.1350 Mass spectrometry; Molecular formula C3□HzqNsOa Theoretical value 547.
22190 Actual value 547.2246 NMR (δ, CDl!3); 1.86 (38, s),
2.38 (3H, s).

4.74(1t1.d, J=61(z), 4.75(
ILd, J=6tlz).

4.77 (III, s), 5.20 (2H, s),
5.80 (IH, dt.

J=11.7Hz, 6Hz), 6.57(IH, d,
J=11.7Hz).

7.00 (IH, s), 7.07-7.40 (7H,
m), 7.33 (LH, t, J=7.8Hz), 7
．． 48 (IH, d, J-7, 8Hz).

7.97 (IH, d, J = 7.8Hz), 8.02 (
IH5s), 8.06(LH,s), 8.21(I
H,s), 8.42 (1B,d,J=2.7t(z) Example 20 (E)-3-((5-imidazolylmethyl)thiophen-2-yl)-2-propene-1- yl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-
5-Pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate 12.3
Hz), 5.20 (2H, s), 5.74 (I
H,s).

5.91 (1B, dt, J=15.6Hz), 6.
49 (1B, d, J = 151 (z), 6.74 (1
1 (, d, J=4Hz), 6.81 (1B, d.

J=4Hz), 6.96(LH,s), 7.0
8 (IH, s), 7.15 (IH, dd, J=7.
5Hz), 7.24(LH, dt, J=7.2Hz
).

7.31 (IH, t, J=8Hz), 7.46 (I
H, d, J = 8Hz).

7.56 (IH, s), 7.97 (1B, d, J=
8Hz), 8.05(LH,3), 8.20(
IH, s), 8.41 (IH, dd, J=5.2H
z) Example 21 2-(4-(diphenylmethyl)piperazinyl)ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate carboxylic acid 350111 g ( 1mmole), (E)
-3-((5-imidazolylmethyl)thiophene-2-
yl)-2-propen-1-ol 220■ (1 mmo
le), dicyclohexylcarbodiimide 309mg
(1,5 mmole), 4-N,N-dimethylaminopyridine 134 flag (1,1 mmole),
Dissolve in 10 mfl of toluene while hot, and heat under reflux for 1 hour. After cooling to room temperature, 20 ml of chloroform is added.

After washing with water, drying with anhydrous sodium sulfate and distilling off the solvent,
Purification was performed by silica gel column chromatography to obtain 400 mg (yield 72.4%) of the title compound.

Melting point, 200.4-201.7°CI
R (cm-', KBr); v CO1698 Not1530.1350 Mass spectrometry; Molecular formula C5゜H,, N, O, S Theoretical value 553
．． 17832 Actual value 553.1786O NMR (δ, CDl!3); 1.84 (3H, s),
2.41 (3H, s).

4.54 (IH, dd, J=12.3Hz), 4.6
7 (IH, dd, J = 1.4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 mg (1 mmole)
, 2-(4-(diphenylmethyl)piperazinyl)ethanol 327■ (1,11IllT101e), dicyclohexylcarbodiimide 309rng (1,5m
mole), 4-N,N-dimethylaminopyridine 1
34 fftg (1.1 mmole) to 1 toluene
Dissolve in 0 mL of hot water and heat under reflux for 1 hour. After cooling to room temperature, 20 m2 of chloroform is added. After washing with water,
After drying over anhydrous sodium sulfate and distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 563 (yield: 89.4%).

Melting point: 171.8-173.3°CI
R (cm-', KBr); v CO1695ν
NO□ 1530. 1350 Mass spectrometry; molecular formula Cs5HxqNsOa theoretical value 629.
30015 Actual value 629.29894 NMR (δ, CDCj!s); 1.85 (3H, s)
, 2.30-2.48 (6H, m), 2.39<3
H,s), 2.53-2.60 (4H,m).

4.05-4.21 (2H, m), 4.17 (IH,
s), 4.75(IH,s), 5.55(IH,s
), 7.13 (IH, dd, J=8°5Hz), 7
．． 17-7.29 (11B, m), 7.39 (1B,
d.

J=8)1z), 7.45 (IH, d, J=8Hz)
, 7.96 (1!I, d.

J=8Hz), 8.03(LH,s), 8.20(
IH,s), 8.42 (IH,d, J=5Hz) Example 22 2-(4-phenylpiperazinyl)ethyl 1,4-dihydro-2,6-simethyl-4-(3-nitrophenyl) -5-pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 mg (1 mmole), 2 (4-phenylpipe Radinyl) ethanol 206■ (1 mmole)
, dicyclohexylcarbodiimide 309mg (1
,5 mmole), 134 mmoles of 4-N,N-dimethylaminopyridine (1,1 mmole), 10 mmoles of toluene
ml while hot, and heated under reflux for 1 hour. After cooling to room temperature, 20 m2 of chloroform is added.

After washing with water, drying with anhydrous sodium sulfate and distilling off the solvent,
Purification by silica gel column chromatography gave the title compound 369 (yield 68.5%).

Melting point; oil IR (cl', KBr); v Co 1695
No. 1530.1350 Mass spectrometry; Molecular formula G3+HaJsOa Theoretical value 539.25320 Actual value 539.25105 NMR (δ, CDCj!s); 1.86 (3H, s)
, 2.4H3)1. s).

2.56-2.63 (68, m) 3.12 (48, t
, J=5tlz).

4.15 (IH, dt, J=11.6Hz), 4.2
2 (18, dt, J = 11.6 Hz), 4.79 (I
H, s), 5.53 (111, s).

6.85 (IH, t, J=8Hz), 6.90 (2H
, d, J=8Hz).

7.14 (LH, dd, J=8.511z), 7.2
2~7.29 (311゜), 7.34 (IH, t,
J=81Lz), 7.50 (IH, d, J=8Hz)
, 8.00 (LH, d, J=8Hz), 8.06 (
LH,s).

8.22 (IH, d, J=2Hz), 8.42 (1B
, dd, J=5.2Hz) Example 23 2-(4-phenylpiperidino)ethyl 1,4-dihydro-2+6-dimethyl-4-(3-nitrophenyl)-
5-pyridylpyridine-3-carboxylate ■ 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350■ (1 mmole), 2= (4- phenylpiperidino) ethanol 205■ (1 mmole), dicyclohexylcarbodiimide 309■ (1.5 mmol)
e) ,4-NUN-dimethylaminopyridine 134■
(1.1 mmole) was dissolved hot in 10 ml of toluene and heated under reflux for 1 hour. After cooling to room temperature, add 20 mj of chloroform! Add. After washing with water, the residue was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 220 mg (yield: 41%) of the title compound.

Melting point; oil IR (am-', KBr); v CO1696
NOx 1530.1350 Mass spectrometry; Molecular formula C1Hx4NaOa Theoretical value 538.25795 Actual value 538.25683 NMR (δ, CDCj!3); 1.60-1.82 (
4H, m), 1.86 (3H, s), 2.06~2
．． 16 (2H, m) 2.42 (3H, s).

2.45-2.50 (IH, m), 2.55-2.6
4 (2H, m).

2.92-3.02 (2H, m), 4.09-4.2
6 (2H, m).

4.80 (IH, s), 5.58 (IH, s), 7
．． 06 (IH, dd.

J=8.5Hz), 7.18-7.29 (6H, m)
, 7.35 (IH.

t, J=9Hz), 7.39(LH,d, J=9Hz
), 8.01 (IH.

d, J=9Hz), 8.06 (IH, s), 8
．． 22 (IH, d, J=2Hz), 8.42 (IH
, dd, J=5,2)1z) Example 24 2-(N-benzyl-N-methylamino)ethyl 1.4
-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylate I (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5- 350 mg (1 mmole) of pyridylpyridine-3-carboxylic acid, N-benzyl-N-
Methylethanolamine 182■ (1,1 mmole)
, dicyclohexylcarbodiimide 309 mg (1,5
134 mg (1,1 mmole) of NUN-dimethylaminopyridine was added to 1 mmole of toluene.
0mj! Dissolve while hot and heat under reflux for 1 hour. After cooling to room temperature, 20 mf of chloroform is added. After washing with water, the residue was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound 403 (yield: 80.9%).

Melting point; oil IR (am-', KBr); v CO1695
ν No, 1530.1350 Mass spectrometry; molecular formula G! 9H3°N404 theoretical value 498.
22666 Actual value 498.22511 NMR (δ, CDCj!s); 1.86 (3H, s)
, 2.19 (3H, s).

2.38 (3H, s), 2.55 (LH, dd, J=
15.6Hz).

3.47 (2H, s), 4.13 (2H, t, J=6
Hz), 4.78 (IH, s), 5.55 (11 (
, s), 7.16 (III, dd, J=7.5Hz)
, 7.22-7.30 (7H, m), 7.44 (1
8,d.

J=7H2), 7.98(lit, d, J=8Hz)
, 8.05 (IH, s).

8.22 (IH, s), 8.43 (LH, d, J=5
Hz) Example 25 2-(1,2,3,4-tetrahydroisoquinoline-2
-yl)ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-
3-carboxylate ■ 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 35 Qmg (1 mmole), 2 (1,2,
3,4-tetrahydroisoquinolin-2-yl) ethanol 177 mm (1 mmole), dicyclohexylcarbodiimide 309 mm (1,5 mmole), 4-N
, N'-dimethylaminopyridine 134 mg (1
, 1 mmole), toluene 10 ml! , and heated under reflux for 1 hour. After cooling to room temperature, 20 ml of chloroform is added. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography to obtain the title compound 378■ (yield 7
4%).

Melting point: 166°C (decomposition) I R (cm-
', KBr) ; v Co 1692SINO□15
32.1348 Mass spectrometry; Molecular formula C1゜H3゜N404 Theoretical value 510.
22666 Actual value 510.22467 NMR (δ, CDCjt'3); 1.86 (3H, s
), 2.41 (311, s).

2.74-2.92 (6H, m), 3.64-3.7
3 (2H, m).

4.24 (IH, dt, J=12Hz, 6Hz), 4
．． 29 (IH, dt.

J=12)1z,6Hz), 4.81(18,s),
5.63 (IH, s).

6.95 (LH, d, J=7.5Hz), 7.06~
7.30 (5H, m).

7.19 (IH, t, J=7Hz), 7.50 (LH
, d, J=7Hz).

7.94 (IH, d, J = 7) 1z), 8.04 (1
8, s), 8.21 (IH, d, J=2.4Hz),
8.42 (LH, dd, J=5Hz.

2.4Hz) Example 26 2-(3,7-dihydro-3,7-dimethyl-IH-purine-2,6-sion-1-yl)ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitro phenyl)
-5-pyridylpyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carboxylic acid 350 mg (1 mmole), 2 (3+7-dihydro3 ,7-dimethylIH-purine-2,6-thion-1-yl)ethanol 224111g (1mmo
le), dicyclohexylcarbodiimide 309■ (1
, 5 mmole), 4 NUN-dimethylaminopyridine 134 [11 g (1.1 mmole) is dissolved in 10 ml of toluene while hot, and heated under reflux for 1 hour. After cooling to room temperature, 20 mj2 of chloroform is added. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography.
The title compound 529■ (yield 95%) was obtained.

Melting point i 198.1-199.9°CI
R (cm-', KBr); v Co 1708
．． 1704.1668νNo, 1530.1352 Mass spectrometry; Molecular formula CzsHzJ706 Theoretical value 557.20223 Actual value 557.20372 NMR (δ, CDCj!z); 1.89 (3B, s)
, 2.37 (3H, s).

3.48 (3H, s), 3.87 (3H, s), 4
．． 12-4.27 (2B, m), 4.33-4.49
(2H, m), 4.80 (IH, 3).

5.66(18,s), 7.22(1!l,dd,
J=7tlz, 2Hz) 7.28 (IH, t, J=7.
5tlz), 7.37 (IH, d, J=7.5Hz
), 7.48(1)1. s), 7.52 (LH
, d, J=7Hz).

7.95 (IH, d, J=7.5Hz), 8.07
(IH, s), 8.27 (18, s), 8.4
3(LH,d,J-2Hz) Example 27 2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-thioxo-7H-purin-7-yl)ethyl 1,4- Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3carboxylate H3 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine- 350 mg (1 mmole) of 3-carboxylic acid, 2-(1,2,3,
6-tetrahydro-1,3-dimethyl-2,6-thioxo-7H-purin-7-yl)ethanol 224■ (1
mmole), dicyclohexylcarbodiimide 30
9 ■ (1,5 mmole), 134 ■ (1,1 mmole) of 4-N,N-dimethylaminopyridine, and 10 mj of toluene! Dissolve while hot and heat under reflux for 1 hour.

After cooling to room temperature, add 20 mj of chloroform! Add. After washing with water, the residue was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound 514 (yield: 92%).

Melting point: 198.6-200.4°CI
R (cm-', KBr); v CO170
0,1652ν NO□ 1528. 1350 Mass spectrometry; Molecular formula CzmHzJ70h Theoretical value 557.20223 Actual value 557.202O2 54N (δ, CDCj23); 1.87 (38
, s), 2.34 (3B, s).

3.38 (3H, s), 3.56 (3H, s),
4.35-4.58 (4H, m), 4.69 (I
H,s), 5.74(IH,s), 7.11(
LH, s), 7.35-7.51 (4H, m), 7
．． 89 (IH, s).

8.04 (IH, d, J=6Hz), 8.25 (I
H,s), 8.47 (LH,d, J=5Hz) Example 28 Methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-pyridylpyridine-3
-Carboxylate 4-(2,3-dichlorophenyl)-3-pyridyl-3
-Buten-2-one 292 ■ (1 mmole), methyl 3-aminocrotonate 575 ■ (5 mmole),
273 cm (2 mmole) of zinc chloride and 500 cm of molecular sieve 4A are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain the target compound 668■ (yield: 85
．． 9%).

Melting point, 158. O~159.3℃I
R (cm-', KBr); v CO1700 mass spectrometry; molecular formula CgaH+JzO□C11t theoretical value 388
．． 07450 Actual value 388.0756 NMR (δ, CDCf3); 1.69 (38, s),
2.4H31(,s).

3.53 (3H, s), 5.30 (lit, s),
5.41 (IH, s).

7.10-7.26 (4H, m), 7.39 (IH,
dd, J-8, 2Hz), 8.12 (IH, s),
8.41 (IH, d, J=4Hz).

Example 29 Methyl 1,4-dihydro-2,6-dimethyl-5-pyridyl-4-(3-trifluoromethylphenyl)pyridine-3-carboxylate 3-(pyridyl-4-(3-)lifluoromethylphenyl )-3-buten-2-one 291■ (1s+mole
), methyl 3-aminocrotonate 575mg (5m
273 mg (2 mmole) of zinc chloride
), 500 mg of Molecular Sheep 4A is heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 361 (yield: 93.2%).

Melting point: 139-140.5°C I R (c
m-', KBr); v CO1700 mass spectrometry;
Molecular formula CtIH1qFzNzOz Theoretical value 388.139
81 Actual value 388.14156 NMR (δ, CDC13); 1.85 (3H, s),
2.38 (38,s).

3.61(3H,s), 4.70(11(,s),
5.53 (IH, s).

7.15 (IH, da, J=8.5Hz) + 7.2
4 (IH, dt, J=8.2H2), 7.32-7.
4H41 (, m), 8.23 (LH.

d, J=2Hz), 8.41 (IH, dd, J=5.
2Hz) Example 30 Methyl 4(2-cyanophenyl)-1,4-dihydro-
2,6-dimethyl-5-pyridylpyridine-3carboxylate 4-(2-cyanophenyl)-3-pyridyl-3-buten-2-one 243 mg (1 mmole), methyl 3-aminocrotonate 575 mg (5 mmole)
, 273 ffkg (2 mmole) of zinc chloride, and 500 mm of molecular sieve 4A in 1,4-
Using dioxane as a solvent, the mixture is heated under reflux for 5 hours. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the title compound 245 was purified by silica gel column chromatography.
(yield 71.2%) was obtained.

Melting point: 142.8-143.9°CI
R(cl', KBr); v CN 2225ν
CO1700 Mass spectrometry; Molecular formula C2゜HI9N30□Theoretical value 345.
14768 Actual value 345.14727 NMR (δ, CDCf3); 1.74 (3H, s),
2.41 (3H, s).

3.55 (3H, s), 5.12 (LH, s),
5.52 (18,s).

7.16-7.21 (2H, m), 7.38 (LH
, dt, J=8Hz.

2Hz>, 7.41-7.50 (3) 1. m),
8.01 (18, dJ=2Hz), 8.40 (L
H, dd, J=5.2Hz) Example 31 Methyl 1,4-dihydro-2,6-dimethyl-4-(
2-furyl)-5-pyridylpyridine-3-carboxylate 4-(2-furyl)-3-pyridyl-3-butene-2-
On 213 ■ (1 mmole), Methyl 3-aminocrotonate 575 ■ (5 mmole), Zinc chloride 273
mg (2 mmole), Molecular Sheep 4A50
0.0 is heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 230 (yield: 74.6%).

Melting point: 161.5-162.8°CI
R (cm-', KIlr); v Co 170
0 mass spectrometry; molecular formula CIIIHIIIN! 03 theoretical value 3
10.13171 Actual value 310.1316O NMR (δ, CDCj!3): 1.87 (3) 1. s
), 2.38 (3H, s).

3.66 (38, s), 4.78 (IH, s),
5.69 (18,s).

5.93 (IH, d, J = 3Hz), 6.22 (I
I, dd, J=2.311z), 7.20 (18,
dd, J=8.4Hz), 7.26(LH, d, J
= 2Hz), 7.42 (LH, d, J = 8Hz),
8.37 (IH, s), 8.43 (IH, d,
J=4Hz) Example 32 Methyl 1,4-dihydro-2,6-dimethyl-5-pyridy-4-thienylpyridin-3-carboxylate 3-pyridy-4-thienyl-3-buten-2-one 2
29 ■ (1 mmole), methyl 3-aminocrotonate 575 ■ (5 mmole), zinc chloride 273 ■ (
2mmole), molecular sieve 4A500■,
The mixture is heated under reflux for 5 hours in an inert gas atmosphere using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 173 (yield: 53%).

Melting point: 19B, 0-199.0°CI
R (cm-', KBr); ! 7 Co 1
670 Mass spectrometry; Molecular formula C+aH+8NzOzS Theoretical value 326.10886 Actual value 326.10108 47N (δ, CDCj!s); 1.93 (31
1,s), 2.35(31(,s).

3.69 (3H, s), 4.69 (1B, s),
5.66 (LH, s).

6.75 (IH, d, J=4Hz), 6.85 (I
H, dd, J = 6.4 Hz), 7.08 (LH, d
d, J=6Hz), 7.18 (LH.

dd, J=7,5)1z), 7.43(1)1. d
, J=7)1z), 8.41(IH,s), 8
．． 43 (LH, d, J = 58.z) Example 33 Methyl 4,5-dipyridyl-1,4-dihydro-2,
6-dimethylpyridine-3-carboxylate 3.4~
Dipyridyl-3-buten-2-one 224■ (1 mmo
le), methyl 3-aminocrotonate 575mg
(5 mmole), zinc chloride 273■ (2IIIll)
Iole) and molecular sieve 4A500 were heated under reflux for 5 hours in 1,4-dioxane as a solvent in an inert gas. Cool to room temperature, neutralize with saturated aqueous sodium hydrogen carbonate solution, and extract with chloroform. After distilling off the solvent,
Purification was performed by silica gel column chromatography to obtain 269 mg (yield: 83.8%) of the title compound.

Melting point: 189.7-190.8°CI
R(cl', KBr); v Co 1700 mass spectrometry; Molecular formula C+ 9HI 9N:lO □ Theoretical value 32
1.14768 Actual value 321.14711 NMR (δ, CDCj!s); 1.84 (3) 1.
s), 2.37 (3H, s).

3.61 (38, s), 4.65 (IH, s), 5.9
4 (IH, s).

7.14 (18,t, J=7Hz), 7.15 (I
H, dd, J.

8.6Hz), 7.26 (IH, d, J=7Hz)
, 7.49 (IH.

d, J=8Hz), 8.26(IH,s), 8
．． 39 (IH, d, J = 6) 1z), 8.41 (1
1, d, J=7) 1z), 8.44 (ltl, s)
Example 34 Methyl 1,4-dihydro-2,6-dimethyl-5 pyridyl-4-(4-quinolyl)pyridine-3-carboxylate 3-pyridyl-4-(4-quinolyl)-3-butene-2
-one 274 ■ (l mmole), methyl 3-aminocrotonate 575 ■ (5 mmole), zinc chloride 2
73mg (2mmole), Molecular Sieve 4A
500 μm was heated under reflux for 5 hours in 1,4-dioxane as a solvent in an inert gas. Cool to room temperature, neutralize with saturated aqueous sodium hydrogen carbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain 324 mg of the title compound (yield 87.5%).
) was obtained.

Melting point: 189°C (decomposition) I R (CIl
l-', KBr); v Co 1695 mass spectrometry; Molecular formula CzJz+N5Oz Theoretical value 371.16333 Actual value 371.1635O NMR (δ, CDCj!3); 1.76(31(,s
), 2.46 (38,s).

3.39 (38,s), 5.51 (18,s),
5.63 (IH, s).

6.94 (IH, dd, J=7.5Hz), 6.9
9 (IH, dt, J=7.2Hz), 7.31 (L
H, t, J=8Hz), 7.49 (IH, d.

J=5Hz), 7.56 (IH, t, J=8Hz)
, 7.89 (11, d.

J=8Hz), 8.00 (IH, d, J=8Hz)
, 8.17 (IH, s).

8.30 (1B, dd, J=5,2tlz), 8.
84(1)1. d, J=5Hz) Example 35 3-cyano-1,4-dihydro-2,6-dimethyl-4
-(3-nitrophenyl)-5-pyridylpyridine l 4-(3-nitrophenyl)-3-pyridyl-3-buten-2-one 0.536 g (2 mmole), 3
-Aminocrotonitrile 0.821 g (10 mmo
le), zinc chloride 0.546 g (4 mmole)
, Molecular Sieve 4A1. Og in inert gas 1,
Heat and reflux for 5 hours using 4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain the title compound 0.
．． 59 g (yield 84.6%) was obtained.

Melting point, 202.8-204.3°CI
R (cm-', KBr); v CN 219
2νNOt 1530. ．． 1350 Mass spectrometry; Molecule 2 C+Jl+J40z Theoretical value 332.12729 Actual value 332.12685 NMR (δ, CDCff1i); 1.84 (3) 1.
s), 2.17(3)1. s).

4.53(1)1. s), 5.81 (IH, s),
7.19 (IH, dd.

J=8.5Hz), 7.28(18,dt, J=8
．． 2Hz), 7.42 (IH, d, J=2Hz),
7.44 (LH+s), 8.07 (III, t.

J=2Hz), 8.09 (IH, d, J=2Hz)
, 8.22 (LH, d.

J=2Hz), 8.42(IH, dd, J=5.2
Hz) Example 36 3-acetyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine 4-(3-nitrophenyl)-3-pyridyl-3-butene- 2-one 268 μ (1 mmole), 4-amino-3-penten-2-one 495 mg (5 mmole)
), 273 mg (2 mmole) of zinc chloride, and 500 mm of molecular sieve 4A were heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent.

Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 121 mg (yield: 34.7%) of the title compound.

Melting point: 160.7-161.9°CI
R (cm-blind, KBr); ! /NOx
1530. 1350 mass spectrometry; molecular formula C2゜HIq
NxOx theoretical value 349.14260 actual value 349.14312 NMR (δ, CDC13); 1.86 (3H, s),
1.98 (3H, s).

2.42 (3H, s), 4.86 (IH, s), 5
．． 96 (1t1.s).

7.22 (IH, dd, J=8.5Hz), 7.31
(IH, d, J = 8Hz), 7.35 (IH, t, J
=8Hz), 7.43(LH,d.

J=8Hz), 8.00(IH,s), 8.01(
18, d, J=8Hz).

8.23 (LH, s), 8.45 (IH, d, J=5
Hz) Example 37 3-benzoyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(3-pyridyl)pyridine ■ 4-(3-nitrophenyl)-3-pyridyl 3-buten-2-one 0.536 g (2 mmole), 3
-amino-1-phenyl-2-buten-1-one 0.1
61 g (10 mmole), zinc chloride 0.54
6 g (4 mmole), molecular sieve 4 A
1.0 mg was heated under reflux for 5 hours in 1,4-dioxane as a solvent in an inert gas. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain 0.424 g of the title compound (yield: 5
1.7%).

Melting point: 172.9-173.8°CI
R (cm-', KBr); v NOz 15
30.1350 mass spectrometry; molecular formula CzsHz+N5(h
Theoretical value 411.15825 Actual value 411.15588 NMR (δ, CDCj!3); 1.85 (38, s)
, 1.98 (31(,s).

4.99 (IH, s), 5.71 (18, s),
7.25-7.47 (8H, m), 7.48 (1
8, d, J=8Hz), 8.00 (IH.

d, J=8Hz), 8.06(IH,s), 8
．． 32(III, s).

8.43(1)1. d, J=5) 1z) Example 38 Methyl 5-(6-chloropyridyl)-1,4-dihydro,-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylate 3-( 6-chloropyridyl)-4-(3-nitrophenyl)-3-buten-2-one 303■ (1 mmole)
, 3-aminocrotonate 575■ (5 mmole)
, 273 μm (2 mmole) of zinc chloride, and 500 mg of molecular sieve 4A were heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent.

Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 229 (yield: 57.5%).

Melting point; 122.5-124.0°CI
R (cm-', KBr); v Co 1680
ν No21530.1350 Mass spectrometry; Molecular formula C2゜HlsCINyO-Theoretical direct
399.09854 Actual value 399.09642 NMR (δ, CDC1x); 1.86 (3H, s)
, 2.39 (3H, s).

3.62 (3H, s), 4.74 (ill, s),
5.58 (IH, s).

7.19 (IH, d, J = 7Hz), 7.22 (I
H, d, J = 7Hz).

7.36 (18,t, J=8Hz), 7.45 (1
1, d, J=8Hz).

7.99 (IH, s), 8.02 (IH, d, J=
8Hz) 8.06(LH,s) Example 39 Methyl 5-(2-chloropyridyl)-1,4-dihydro-2,6-cy)thyl-4-(3-nitrophenyl)pyridine-3-carboxy Rate 3-(2-chloropyridyl)-4-(3-nitrophenyl)-3-buten-2-one 303■ (1 mmole)
, methyl 3-aminocrotonate 575■ (5mmo
le), 273 mmoles of zinc chloride, and 500 mmoles of molecular sieve 4A are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain the title compound 204 (
A yield of 51% was obtained.

Melting point; oil IR (cm-', KBr); v CO1698
No! 1532.1350 Mass spectrometry; Molecular formula CzoH+ acl N304 Theoretical value 399.09547 Actual value 399.10100 99N (δ, CDCj!s); Internal standard Cyclos
ilan-d.

(δ・−0,327) at 100°C.

1.58 (3H, s), 2.31 (3H, s),
3.43 (3H, s).

4.73 (IH+s), 6.90~? -33 (2H1m
) + 7.33-7.48 (2H, m), 7.75 (
IH, s), 7.91 (IH, d.

J=8Hz), 8.19(2)1. m) Example 40 Methyl 1,4-dihydro-2,6-dimethyl-5(6
-Medoxypyridyl)-4-(3-nitrophenyl)pyridine-3-carboxylate 3-(6-medoxypyridyl)-4-(3-nitrophenyl)-3-butene-2
298 mg (1 mmole) of -one, 575 mg (5 mmole) of methyl 3-aminocrotonate, 273 mg (2 mmole) of zinc chloride, and 500 mg of molecular sieve 4A are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature;
Neutralize with saturated aqueous sodium hydrogen carbonate solution and extract with chloroform. After distilling off the solvent, it was purified using silica gel column chromatography to obtain the title compound 290cm (yield 7.
4.5%).

Melting point; oil IR (crfi-', KBr); v Co 1
695v Not 1530, 1350 Mass spectrometry: Molecular formula Cz + Hz + NaOs theory straight 39
5.14808 Actual value 395.14987 NMR (δ, CDCj! 3); 1.85 (3H, s
), 2.38 (3H, s).

3.60 (3H, s), 3.88 (3H, s), 4
．． 72 (IH, s).

5.51 (LH, s), 6.62 (LH, d, J=8
Hz), 7.16 (IH, dd, J=8.2Hz),
7.34 (1M, t, J=8Hz).

7.48 (IFl, d, J = 8Hz), 7.71 (I
H, d, J = 2Hz).

8.00 (IH, d, J=8Hz), 8.06 (il
l,s) Example 41 Methyl 1,4-dihydro-2,6-dimethyl-5(2
-Methoxyphenyl)-4-(3-nitrophenyl)pyridin-3-carboxylate■ 3-(2-methoxyphenyl)-4-(3-nitrophenyl)-3-buten-2-one 297■ (1 mmole
), methyl 3-aminocrotonate 575 mg (
5 mmole), zinc chloride 273 mg (2 mmol)
e) 500 mg of molecular sieve 4A is heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent,
Purification was performed by silica gel column chromatography to obtain 216 mg (yield 55%) of the title compound.

Melting point: 176.4-177.7°CI
R (cm-', KBr); v NH3370,
Co 1705 Noz 1535.1345 Mass spectrometry; Molecular formula CztH2tNtOs Theoretical value 394.
15283 Actual value 394.15187 NMR (δ, CDCj!s)i 1.70 (3H, bs
), 2.40 (3H, s) 3.57 (3H, s),
3.74-3.97 (3H, b), 4.82 (IH,
bs), 5.42 (LH, bs), 6.60-6.
92 (48, b), 7.16 (LH, td, J=8H
z, 2Hz), 7.25 (LH, t, J=8■z)
, 7.36 (IH, d, J=8Hz), 7.57 (
ltl, d, J=8Hz), 8.01 (111,s)
Example 42 Methyl 1,4-dihydro-2,6-dimethyl-5(2
-fluorophenyl)-4-(3-nitrophenyl)pyridine-3-carboxylate 3-(2-fluorophenyl)-4-(3-nitrophenyl)-3-butene-2
-one 285 ■ (1 mmole), methyl 3-aminocrotonate 575 ■ (5 mmole), zinc chloride 2
73■ (2mmole), molecular sieve 4A50
0 mg was heated under reflux for 5 hours in 1,4-dioxane as a solvent in an inert gas. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 242 (yield: 63%).

Melting point i 153.0-153.1°CI
R (c+n-', Br); v NH3360,C
o 1690 しNO□ 1535.1345 Mass spectrometry; molecular formula CxtH+JNzOn theoretical value 382.
13284 Actual value 382.13492 NMR (δ, CDCj2s); 1.73 (311,s
), 2.39 (3FI, s).

3.58 (3H, s), 4.79 (1B, s), 5
．． 40 (IH, bs).

6.81-6.90 (LH, b), 6.92-7.0
2 (2H, m).

7.13-7.22 (IH, m), 7.27 (IH,
t, J=8Hz).

7.41 (IH, d, J=8Hz), 7.94 (IH
, ddd, J=8)1z.

2Hz, 1tlz), 8.00 (IH, t, J=2H
z) Example 43 Methyl 1,4-dihydro-2,6-dimethyl-4(3
-nitrophenyl)-5-thienylpyridine-3-carboxylate 3-pyridyl-4-thienyl-3-buten-2one 27
3■ (1 mmole), methyl 3-aminocrotonate 575 mg (5 mmole), zinc chloride 273 m
g (2mmole), molecular sieve 4A500
(1) using 1,4-dioxane as a solvent in an inert gas,
Heat to reflux for 5 hours. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform.

After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 206 (yield: 61%).

Melting point: 144.2-144.4°CI
R(cl', KBr); v NH3370
, Co 1650ν N (h 1550.1355 Mass spectrometry; Molecular formula Cl9H1lIN202S Theoretical value 33
8.10886 Actual value 338.10106 55N (δ, CDCf5); 2,11 (3tl, s
), 2.37 (3H, s).

3.65 (3H, s), 4.88 (IH, s), 5
．． 57 (LH, bs).

6-66 (LH+ddlJ=4Hz, IHz) 16.8
8 (IH, dd.

J=5H2,4H2), 7.12(IH, dd, J=
5H, z, IHz).

7.38 (18, t, J=8H, z), 7.62 (I
H, dt, J = 8Hz.

IHz), 8.02 (IH, ddd, J=8Hz, 2
Hz, IHz) 8, 14 (LH, t, J=2Hz) Example 44 Methyl 1,4-dihydro-2,6-dimethyl-5(2
-furyl)-4-(3-nitrophenyl)pyridine-3
-Carboxylate H 3-(2-furyl") -4-(3-nitrophenyl)
-3-buten-2-one 257 [ng (1 mmol)
e), methyl 3-aminocrotonate 575■ (5mm
ole), 273 mmoles of zinc chloride, and 500 mg of molecular sieve 4A in an inert gas solution.
Using dioxane as a solvent, the mixture is heated under reflux for 5 hours. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the title compound 289 was purified by silica gel column chromatography.
(2) (yield 82%) was obtained.

Melting point? 173.2~173.9°CI
R (cm-weight, KBr); v NH3370,C
O1650 NOt 1530.1350 Mass spectrometry; molecular formula C+qll+5NzOs theoretical value 354
．． 12154 Actual value 354.12038 NMR (δ, CDCfa); 2.27 (3H, s),
2.36 (3H, s).

3.68 (3H, s), 5.02 (IH, s), 5
．． 59 (LH, bs).

6.07 (IH, d, J=3Hz), 6.31 (IH
, dd, J=3) 1x.

2Hz), 7.31 (IH, d, J=2Hz), 7
．． 37(L[(,t.

J=8Hz), 7.99(LH, ddd, J=8Hz
, 2Hz, IHz).

8.15 (IH, t, J=2Hz) Example 45 Methyl 1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)-5-pyridazinylpyridine-3
-carboxylate 4-(3-nitrophenyl)-3-pyridazinyl-3-
Buten-2-one 213mg (0.84mmole)
, methyl 3-aminocrotonate 484tng (4,
2 mmole), zinc chloride 343■ (2 mmole)
, 500 mg of molecular sieve 4A was heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent.

Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 280.mu. (yield: 91%).

Melting point; 94.8°C IR (cm-', KBr); v CO1680
CINO□ 1528.1348 Mass spectrometry; Molecular formula CI9 old 8N404 Theoretical value 366, 13277 Actual value 366.13126 NMR (δ, CDCf: +); 2.18 (3H, s)
, 2.40 (3H, s).

3.66 (3H, s), 5.25 (IH, s), 6
．． 04(ltl,s).

7.23 (IH, dd, J=8.7Hz, 2.4Hz)
, 7.34 (1!l.

dd, J=8.7Hz, 5.1Hz), 7.35(L
H, t, J=7.8Hz), 7.61(ltl, d,
J=7.8Hz), 7.98(IH,d,J-7,8
8,z) + 8.12(LH,s), 8.98(IH
, dd, J=5. IHz, 1.5Hz) Example 46 Methyl 1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)-5-(3-quinolyl)pyridine-3-carboxylate H 4-(3-nitrophenyl)-3-(3-quinolyl)-
3-buten-2-one 302 mg (1 mmole)
, 3-aminocrotonate 575 mg (5 mmol
e) 273 mg (2 mmole) of zinc chloride and 500 ml of molecular sieves are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain 300 m
g (yield 80.8%) was obtained.

Melting point: 115°C IR (cm-', KBr); ! l CO169
5S Noz 1530.1350 Mass spectrometry; Molecular formula CzJzINsOa Theoretical value 415.15316 Actual value 415.15194 NMR (δ, CDCf*); 1.93 (3H, s),
2.43 (38,s).

3.63 (3H, s), 4.92 (18, s), 5
．． 64 (18, s).

7.33(1)1. t, J=8FIz), 7.47
(IH, d, J=8Hz).

7.52 (ltl, t, J=81f), 7.67~7
．． 74 (3H, m).

8.01 (1B, d, J=8Hz), 8.09 (1)
1. d, J=8Hz).

8.12 (LH, s), 8.57 (LH, d, J=2
Hz) Example 47 Methyl 1,4-dihydro-2,6-dimethyl-4(3
-nitrophenyl)-5-pyrazinylpyridine-3-carboxylate 4-(3-nitrophenyl)-a-pyrazinyl-3-buten-2-one 253 mg (1 mmole), 3-
Aminocrotonate 575 mg (5 mmole)
, 273 cm (2 mmole) of zinc chloride, and 500 cm of molecular sieve 4A were heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature;
Neutralize with saturated aqueous sodium hydrogen carbonate solution and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain the title compound 271■ (yield 7).
7.3%).

Melting point: 134.9-136.1°CI
R (cm-', XBr); v CO1670ν
N (h 1530.1350 Mass spectrometry: Molecular formula Cl9H1llN404 Theoretical value 366
．． 13277 Actual value 366.13473 NMR (δ, CDC23); 2.18 (3B, s),
2.40 (3H, s).

3.66 (31, s), 5.25 (IH, s), 5
．． 68 (ltl, s).

7.35<IW, t, J=8Hz), 7.59(1)
1. d, J=8Hz).

7.97 (18, d, J=8Hz), 8.10 (LH
, s), 8.30 (IH, d, J=3Hz), 8.
34 (IH, d, J=2Hz), 8.51 (18, d
d, J=3.2Hz) Example 4 Day Methyl 1,4-dihydro-2,6-dimethyl-4(3
-nitrophenyl)-5-(2-pyridyl)pyridine-
3-carboxylate H 4-(3-nitrophenyl)-3-(2-pyridyl)-
3-buten-2-one 268 mm (1 mmole), methyl 3-aminocrotone) 575 mg (5 mmol
e) 273 mmoles (2 mmoles) of zinc chloride and 500 mmoles of Molecular Sheep-4A are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain the title compound 292 (
A yield of 80% was obtained.

Melting point: 156.6-158.1°CI
R (cm-', Br); v NH3340,
CO1665ν NO□ 1535. 1345 Mass spectrometry; Molecular formula CzoH+J:+L Theoretical value 365.13751 Actual value 365.13973 NMR (δ, CDCfz); 2.0? (3H,s),
2.39 (3H, s).

3.63 (3H, s), 5.23 (IH, s), 5
．． 54 (IH, s).

6.97 (IH, d, J=8Hz), 7.05 (II
I, dd, J = 8Hz.

5Hz), 7.31 (LH, t, J=8Hz), 7
．． 50 (IH, td.

J=811z, 2Hz), 7.53(1B, d, J=
811z), 7.95 (IH, dt, J=8Hz, 2
Hz), 8.07 (IH, t, J=2Hz).

8.55 (IH, d, J=5Hz) Example 49 Methyl 1,4-dihydro-2,6-dimethyl-4(3
-nitrophenyl)-5-(4-pyridyl)pyridine-
3-carboxylate 4-(3-nitrophenyl)-3-(4-pyridyl)-
3-buten-2-one 268 mg (1 mmole)
, methyl 3-aminocrotonate 575 mg (5 mm
ole), zinc chloride 273mg (2mmole),
Molecular sieve-4A 500mg in inert gas 1
, 4-dioxane as a solvent and heated under reflux for 5 hours.

Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 300 ml of the title compound (yield: 82%).

Melting point: 165°C (decomposition) I R (c ``'
, KBr); v CO1680S Noz 15
30.1350 Mass spectrometry; Molecular formula C2゜H+JzOs Theoretical value 365.13751 Actual value 365.13897 NMR (δ, CDCf z)i 1.95 (38, s)
, 2.39 (3H, s).

3.64 (38, s), 4.86 (IH, s), 5
．． 6H1)1. s).

6.93 (2H, dd, J=5Hz, 2Hz), 7.
34 (IL t, J=8Hz), 7.47 (IH, d
, J=8Hz), 8.00(LH, ddd.

J=8Hz, 2tlz, IHz), 8.07 (18,
t, J=2Hz).

8.45 (2H, dd, J=5) 1z, 2Hz) Example 50 2-(N-benzyl-N-methylamino)ethyl 1.4
-dihydro-2,6-simethyl-4-(3-nitrophenyl) -5-(4-pyridyl)pyridine-3-carboxylate■ 1.4-dihydro-2,6-simethyl-4-(3-nitrophenyl) -5-(4-pyridyl)pyridine-3-carboxylic acid 350 μm (1 mmole), N-benzyl-
N-methylethanolamine 165■ (1 mmole)
, dicyclohexylcarbodiimide 309 mg (
1.5 mmole), 4-N,N-dimethylaminopyridine 134 mmole (1.1 mmole) was added to 10 m of toluene.
1. Dissolve while hot and heat under reflux for 1 hour. After cooling to room temperature, 20 ml of chloroform is added. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography to obtain the title compound 5.
02■ (yield 100%) was obtained.

Melting point; oil r R (cm-', KBr); v Co 169
5 NOx 1530.1350 Mass spectrometry; Molecular formula C29H3°N404 Theoretical value 498.
22666 Actual value 498.2285O NMR (δ, CDCj23); 1.94 (3H, s)
, 2.20 (3H, s).

2.38 (38, s), 2.58 (IH, dd, J=
9.6)1z).

2.65 (11(, dd, J=9.6Hz), 3.4
9 (2H, s).

4.16 (2H, t, J = 61 (z), 4.85 (3
H, s), 5.65 (LH, s), 6.91 (28
, d, J=7Hz), 7.15-7.30 (6H, m
), 7.46 (IH, d, J=811z), 7.9
7 (IH, d.

J=8)1z), 8.07(LH,s), 8.
45(2H,d,J=7)1z) Example 51 (E)-3-phenyl-2-flopen-1-yl 1.4
-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-( 3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylic acid 700 μ (2 mmole
) in 10 m2 of anhydrous tetrahydrofuran, and 220 mg (2.2 mmole) of triethylamine are added. Under water cooling, ethyl chloroformate 228■ (2.1 mmo
1) dropwise and stirred for 30 minutes. Under water cooling, add 268 μm (2 mmole) of (E)-cinnamyl alcohol,
Stir for 2.5 hours. The reaction solution was washed with saturated brine, dried over anhydrous sodium sulfate, and tetrahydrofuran was distilled off under reduced pressure. Purification was performed by silica gel column chromatography to obtain 280 mg (yield 30%) of the title compound.

Melting point i 158.0-159.5'C
IR (cm-low, KBr); v Co 1698
CNO□ 1530.1350 Mass spectrometry; molecular formula Cz11HzsNaOa theory direct 4
67.18446 Actual value 467.18453 NMR (δ, CDCj23); 1.94 (3H, s)
, 2.41 (3H, s).

4.67 (IH, dd, J=12.7Hz), 4.7
5 (LH, dd, J = 12.7) 12), 4.89 (
1)1. S), 5.89 (IH, s).

6.23(1)1. dt, J=15.5Hz), 6.
54 (18, d, J=15Hz), 6.91 (2H
, d, J=7Hz), 7.25-7.36 (68,
m), 7.49 (IH, d, J=8Hz), 8
．． 00 (IH, d.

J=8Hz), 8.10(LH,s), 8.4
4(2H, d, J=7Hz) Example 52 2-(4-phenylpiperazinyl)ethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridyl ) Pyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylic acid 350 mg (1 mmole), 2-(4-
phenylpiperazinyl) ethanol 206■ (l mm
ole), dicyclohexylcarbodiimide 309
mg (1,5 mmole), 134 mg (1,1 mmole) of 4-N,N-dimethylaminopyridine are dissolved in 10 mj2 of toluene under heating, and heated under reflux for 1 hour.

After cooling to room temperature, 20 ml of chloroform is added. After washing with water, drying with anhydrous sodium sulfate, distilling off the solvent, and purifying with silica gel column chromatography.
The title compound 471■ (yield 100%) was obtained.

Melting point; oil'c I R (cm-', KBr); νCo 1694SNO□ 1532.1350 Mass spectrometry: Molecular formula C31H3JsOa Theoretical value 539.25321 Actual value 539.25378 NMR (δ, CDCj! 3); 1.94 (3H,s
), 2.41 (3H, s).

2.50-2.82 (6H, m), 3.10-3.
27 (4H, m).

4.20-4.40 (2H, m), 4.88 (1B
, s), 5.66 (IH, s), 6.85-6.9
8<48. m), 7.23~? , 32(5)1. s),
7.34 (LH, t, J=7Hz), 7.49
(IH, d.

J=7Hz), 8.00 (IH, d, J=7Hz)
, 8.06 (LH,s).

8.46 (IH, d, J-6,3Hz) Example 53 Allyl 1,4-dihydro-2,6-dimethyl-4-(
3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridyl)pyridine-3- Carboxylic acid 350mg (1mmole), allyl alcohol 58mm (1mmole), dicyclohexylcarbodiimide 309mg (1.5mmole), 4
N,N-dimethylaminopyridine 134■ (1,1mm
ole), toluene 10m! ! , and heated under reflux for 1 hour. After cooling to room temperature, add 20 mI of chloroform! , add. After washing with water, the residue was dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound 39k (yield: 100%).

Melting point: 185.3-186.7°CIR
(C111-', KBr); v Co 1696
ShiN (h 1526.1348 Mass spectrometry; Molecular formula C2□H2□N304 Theory I direct 39
1.15317 Actual value 391.15342 NMR (δ, CDCj'+); 2.08 (3H, s),
2.41 (3H, s).

4.54CIII, dd, J=1311z, 6Hz),
4.62 (LH, dd.

J=13Hz, 6Hz), 4.94(IH,s),
5.20 (18, dd.

J=10Hz, 21(z), 5.22(IH, dd,
J=1.9Hz, 2)1z).

5.82-5.97 (IH, m), 5.90 (IH,
s), 7.17 (2H, d, J=6Hz), 7.3
8 (1B, t, J=7.8Hz).

7.51 (LH, d, J = 7.8Hz), 8.04 (
1B, d, J=7.8H2), 8.09(IH,S)
, 8.46 (IH, d, J=6Hz) Example 54 2-(phenoxy)ethyl 1,4-dihydro-2゜6
-Simethyl-4-(3-nitrophenyl)-5-(4-
pyridyl)pyridine-3-carboxylate 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(4-pyridyl)pyridine-3-carboxylic acid 350 μ (1 mmole), 2-( phenoxy) ethanol 138 mmole (1 mmole), dicyclohexylcarbodiimide 309 mmole (1.5 mmole)
, 4-NUN-dimethylaminopyridine 134 mg
(1.1 mmole) was dissolved in 10 m2 of toluene while hot and heated under reflux for 1 hour. After cooling to room temperature, 20 ml of chloroform is added. After washing with water, rinse with sulfuric anhydride)
After drying with IJum and distilling off the solvent, the title compound was purified by silica gel column chromatography.
A yield of 100% was obtained.

Melting point; so'c IR (cm-', KBr); v Co 169
8S NOx 1528.1350 Mass spectrometry; Molecular formula CzdhsN+Os Theoretical value 471.17938 Actual value 471.18037 NMR (δ, CDCj!3); 1.97 (3H, s)
, 2.40 (3H, s).

4.03-4.18 (2!l, m), 4.30-4.
39 (LH, m).

4.42-4.52 (IH, m), 4.87 (III
, sL 5.78 (18, s) + 6.85 (2H, d
, J=711z), 6.93-7.00 (IH, m)
, 6.95 (2B, d, J=6.5Hz), 7.1
9 (IH.

t, J=8.2)1z), 7.28(2H,t,J=
7Hz), 7.46 (LH, d, J=8.2Hz),
7.94 (111, s), 8.44 (211°d,
J=6.5Hz) Example 55 (E)-3(4-(1-imidazolylmethyl)phenyl)-2-propen-1-yl 1,4-dihydro-2,
6-Simethyl-5-(2-furyl)-4-(3-nitrophenyl)pyridine-3-carboxylate H 3-(2-furyl)-4-(3-nitrophenyl)-3
-Buten-2-one 257■ (1 mmole), (E)
-3-(4-(1-imidazolylmethyl)phenyl)-
2-propen-1-yl 3-aminocrotonate 88
5■ (3 mmole), Zinc chloride 409■ (2 mmole)
le) Molecular sieve 4A500■ is heated under reflux for 5 hours in 1,4-dioxane as a solvent in an inert gas. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent,
After purification and preparation using silica gel column chromatography, the title compound was recrystallized from methanol (yield: 3
9%).

Melting point: 81°C (decomposition) I R (cm-', KBr); v Co
1690ν Not 1528.1350 Mass spectrometry; Molecular formula C: 1IH28N40S Theoretical value 536
．． 20593 Actual value 536.20635 NMR (δ, CDCjh); 2.27 (3H, s),
2.39 (3tl, s).

4.68 (IH, dd, J=12.5Hz, 6Hz),
4.80 (IH.

dd, J=12.5To, 6Hz), 5.05(IH
,s), 5.22(LH,s), 5.66(LH,
s), 6.05 (LH, d, J=3.28Z), 6
．． 25-6.35 (2H, m), 6.54 (IH.

d, J=16Hz), 7.00(Ill,s), 7
．． 19 (2H, d, J=9Hz), 7.24 (IH,
s), 7.30 (18, d, J=2Hz).

7.35 (IH, t, J=6.411z), 7.38
(2H, d, J=9)Iz).

7.68 (111, d, J=6.4Hz), 7.97
(18,d, J=6.4Hz), 8.16(LH,s
), 8.18(11(,s) Example 56 1.4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(2-pyridyl)pyridine-3-carbonitrile 4-( 3-nitrophenyl)-3-(2-pyridyl)-
3-buten-2-one 268 mg (1 mmole)
, 3-aminocrotonitrile 410mg (5mmol
e) 273 mmoles of zinc chloride and 500 mg of molecular sieve 4A are heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, it was purified by silica gel column chromatography to obtain the title compound 160
A yield of 48%) was obtained.

Melting point; 137.3-138.5°CI
R (cm-', KBr); v NH3390C
N 2190νN0t1530.1355 Mass spectrometry; Molecular formula Cl9)116N40□Theoretical value 332
．． 12730 Actual measurement direct 332.12778 NMR (δ, CD (, e i); 2.03 (3H, s
), 2.17 (3H, s).

5.03 (IH, s), 5.56 (IH, s), 6
．． 94 (Ill, d.

J=8H2), 7.05(IH, dd, J=8Hz,
5Hz), 7.39(LH,t,J=8)1z),
7.50 (ill, td, J=8Hz, 2Hz).

7.52 (III, d, J=811z), 8.02 (
IH, dt, J = 8Hz.

2Hz), 8.09(1)1. t, J=2Hz),
8.52 (IH, d.

Example 57 N,N-diethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(2-pyridyl)pyridine-3-carboxamide ■ 4-(3- Nitrophenyl)-3-(2-pyridyl)-
3-buten-2-one 268■ (1 mmole), N,
N-diethyl 3-amino-2-butenamide 180mg
(5 mmole), zinc chloride 273■ (2 mmole)
e) 500 mg of molecular sieve 4A is heated under reflux for 5 hours in 1,4-dioxane as a solvent in an inert gas. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent,
Purification by silica gel column chromatography gave the title compound 259 (yield 64%).

Melting point; oil'c IR (cm-', KBr); ! / C0168
5 Noz 1530.1350 Mass spectrometry; Molecular formula Cs+HsJs04 Theoretical value 539.25321 Actual value 539.25378 NMR (δ, CDCfz); 0.68-1.13 (6
11,m), 1.85(3H,s), 2.09(3
H, s), 3.14-3.49 (48, m).

4.97 (IH, s), 5.10 (LH, bs),
6.96 (IH, dd.

J-8H2, 5H2), 7.02 (Ill, d, J=
8Hz), 7.33 (IH, t, J=8Hz), 7
．． 45 (IH, td, J=8Hz, 2)1z).

7.57 (LH, d, J=8Hz), 7.94 (18
, ddd, J=8Hz.

2Hz, IHz), 8.07 (IH, t, J=2Hz
), 8.46 (ill.

d, J=5Hz) Example 58 3-benzoyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-(2-pyridyl)
Pyridine 4-(3-nitrophenyl)-3-(2-pyridyl)-
3-buten-2-one 268 mg (1 mmole)
, 3-amino-1-phenyl-2-buten-1-one 8
05 mg (5 mmole), zinc chloride 273■ (
2mmole), molecular sieve 4A500■,
The mixture is heated under reflux for 5 hours in an inert gas atmosphere using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 288 (yield: 70%).

Melting point? 202.3~206.8°CI
R (cm-', KBr); v NH3310C
O1680 No! 1525.1345 Mass spectrometry; molecule 2 Czsl (z + Nz (h theoretical value 411
．． 15827 Actual value 411.15832 NMR (δ, CDCf5); 1.86 (3H1s)+
2.21 (3H, s).

5.32 (Ills), 5.64 (IH, bs), 7
．． 02(ill, d.

J=8Hz), 7.05(IH, ddd, J=8Hz
, 511z, IHz).

7.27-7.58 (8H1m) + 7.96<111
．． ddd, J=8Hz.

2Hz, IHz), 8.05(1)1. t, J=2H
z), 8.54 (Ill.

d, J=5Hz) Example 59 Acetyl-1,4-dihydro-2,6-dimethyl-4-
(3-nitrophenyl)-5-(2-pyridyl)pyridine 4-(3-nitrophenyl)-3-(2-pyridyl)
-3-buten-2-one 268 mg (1 mmole
), 4-amino-3-penten-2-one 495■ (5
mmole), zinc chloride 273 mg (2 mmol)
e) Molecular Sheep 4A500 is heated under reflux for 5 hours in an inert gas using 1,4-dioxane as a solvent. Cool to room temperature and add saturated sodium bicarbonate water? Neutralize with solution and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 49 (yield: 14%).

Melting point: 192.5-193.1'C
I R (cm-', KBr); v Nl (332
0νNo! 1530.1340 Mass spectrometry; molecular formula C2°H+qN303 theoretical value 349.
14260 Actual value 349.14319 NMR (δ, CDCf3); 2.04 (3H, s),
2.18 (3H, s).

2.42 (38, s), 5.34 (IH, s), 5
．． 60 (LH, bs).

6.96 (IH, dd, J=8Hz, IHz), 7.
09 (IH, dd.

J=8Hz, 5Hz), 7.31(IH,t, J=8
Hz), 7.48 (IH, d, J=8Hz), 7.
53 (IH, td, J=8Hz, 2Hz).

7.96 (LH, d, J=8Hz), 7.99 (IH
, t, J=2Hz).

8.59 (IH, d, J=5Hz) Example 60 2.2.2-Trifluoroethyl 1,4-dihydro-
2,6-dimethyl-4-(3-nitrophenyl)-5-
(2-pyridyl)pyridine-3-carboxylate 4-(3-nitrophenyl)-3-(2-pyridyl)-
3-buten-2-one 268 mg (1 mmole)
, 2.2.2-trifluoroethyl 3-aminocrotonate 915■ (5 mmole), zinc chloride 273
mg (2 mmole), molecular sieve 4A500
(1) using 1,4-dioxane as a solvent in an inert gas,
Heat to reflux for 5 hours. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform.

After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 101 mg (yield: 23%) of the title compound.

Melting point? 132.1~134.4°CI
R (cm-', KBr); v NH3390ν
C01960Not 1525.1350 Mass spectrometry; Molecular formula C2□HIllN304 Theoretical value 433.12491 Actual value 433.12453 NMR (δ, CDCj!a); 2.05 (3H, s)
, 2.41 (3H, s).

4.24-4.53 (2H, m), 5.21 (IH,
s), 5.67 (IH, bs), 6.93 (18,
d, J=8Hz), 7.07 (IH.

ddd, J=8Hz, 5Hz, IHz), 7.31(
1)1. t, J=8Hz).

7.49 (IH+d, J=8Hz), 7.51 (IH,
td, J=8Hz.

2Hz), 7.97 (IH, dt, J=8Hz, 2H
z), 8.07 (IH, t, J=2Hz), 8.5
6 (LH, d, J=511z) Example 61 1,4-dihydro-2,6-dimethyl-3-nitro4-
(3-nitrophenyl)-5-(2-pyridyl)pyridine 11 4-(3-nitrophenyl)-3-(2-pyridyl)-
3-buten-2-one 268■ (1 mmole), 2-
Amino-1-nitro-1-propene 3-aminocrotonate 510 mg (5 mmole), zinc chloride 27
3■ (2 mmole), molecular sieve 4A500
(1) using 1,4-dioxane as a solvent in an inert gas,
Heat to reflux for 5 hours. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform.

After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 98■ (yield 28%).

Melting point: 195.6-199.2°CI
R(cl', KBr); v NO21530,
1350 mass spectrometry; molecule 2〇+ IHI 6N404 theoretical value 352.11712 actual value 352.11891 NMR (δ, CDCf5); 2.06 (3H, s),
2.64 (3H, s).

5.70 (IH, s), 5.98 (IH, bs),
6.95 (LH, d.

J=8Hz>, 7.11CLH, ddd, J=8Hz
, 5 (Iz, 111z).

7.33 (18,t, J=8Hz), 7.54 (LH
, td, J=8Hz.

2Hz), 7.55 (IH, d, J=8Hz), 7
．． 98 (IH, ddd.

J=8H212H2lIH2) 18.08(1B, t,
J=2Hz).

8.58 (IH, d, J = 8 Hz) Example 62 Methyl 1,4-dihydro-2,6-dimethyl-4(3
-nitrophenyl)-5-(3-pyridyl)pyridine-
3-sulfinate 4-(3-nitrophenyl)=3-(2-pyridyl)
-3-buten-2-one 268 mg (1 mmole
), methyl 3-amino-2-propenesulfinate 675 mmole (5 mmole), zinc chloride 273 mg (
2mmole), molecular sieve 4A500■,
The mixture is heated under reflux for 5 hours in an inert gas atmosphere using 1,4-dioxane as a solvent. Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain the title compound 150.mu. (yield: 39%).

Melting point: 210.8-211.5℃IR(
cm-', KBr); J/NH3350νNO
□ 1530.1350 Mass spectrometry; Molecular formula C+JtJsO4S Theoretical value 385.10960 Actual value 385.10109 62N (δ+CDCji!3): 2.07 (3H,
s), 2.39 (3H, s).

2.68 (3H, s), 5.30 (IH,!+),
6.05 (IH, bs).

7.00 (LH, d, J=8Hz), 7.07 (IH
, dd, J=8)1z.

5Hz), 7.35 (IH, t, J=8!Iz),
7.53 (IH, td.

J=8Hz, 2Hz), 7.62(IH, d, J=8
Hz), 8.01 (18, d, J=8Hz), 8.
15 (18, t, J=2Hz), 8.53 (IH, d
, J=5Hz) Example 63 Methyl 1,4-dihydro-2,6-dimethyl-4(3
-methoxyphenyl)-5-(2-pyridyl)pyridine-3-carboxylate H 4-(3-methoxyphenyl)-3-(2-pyridyl)
-3-buten-2-one 268 mg (1 mmole
), methyl 3-aminocrotonate 575■ (5mm
ole), zinc chloride 273mg (2mmole)
, molecular sieve 4A500■ in an inert gas.
Heat and reflux for 5 hours using 4-dioxane as a solvent.

Cool to room temperature, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 210 mg (yield: 60%) of the title compound.

Melting point; 164.2-164.6°CI
R(cl', KBr); v CO1690 mass spectrometry; molecule 2〇z+Hz□NgO+theoretical value 350.16
302 Actual value 350.16082 NMR (δ, CDCl 3); 2.07 (3H, s
), 2.35 (3H, s).

3.63 (3H, s), 3.71 (3H, s), 5
．． 02(1)1. s).

5.45 (IH, bs), 6.66 (LH+dd, J
=8Hz, 2Hz).

6.79 (IH, t, J=2Hz), 6.83 (LH
, d, J=8Hz).

6.97 (18, d, J=8Hz), 7.03 (lt
l, ddd, J=81! z.

5H2, IH2), 7.11 (18,t, J=8Hz
), 7.48 (ill.

td, J=8Hz, 2Hz), 8.54(lfl, d
, J = 5 Hz) Test example (platelet aggregation inhibitory effect) The test drug was dissolved in 50% HCO-60 (niccol)/ethanol, then diluted with physiological saline (maximum solvent concentration 0).
．． Arachidonate sodium salt was used as the other drug (5%). Weight 2.3-2.6 kg for the test
Japanese white male rabbits were used.

From the carotid artery of a rabbit, 3.8% per volume 9 under no anesthesia.
The blood sample was collected and centrifuged at 130xg, 20°C for 15 minutes to obtain platelet-rich plasma (PRP), and the lower layer was further centrifuged at 650xg, 20°C for 10 minutes to obtain platelet-poor plasma (PPP).

The test drug was 10 μ2 added to PRP 200 μ.
After 30 min incubation at 37°C, AA (1 m
10 ui of M) was added to induce aggregation, and the reaction was measured using an agglomerometer (NKK, PAT-4A).

(Antihypertensive effect) The test drug was 50% of lIC0-60 (Nippon Chemicals)
After dissolving in ethanol solution, dilute with physiological saline until the liquid volume is 1 mjl! /kg (final solvent concentration 1% or less). Animals are 20-25 weeks old male SH
R (Japanese rat) was used. Systemic blood pressure was determined by inserting a polyethylene cannula into the abdominal aorta via the caudal artery under ether anesthesia according to the method of Nakatari et al. After awakening from anesthesia, the patient was restrained in a cage using a pressure transducer (Nihon Kohden, ?1PU-0).
,5) Piezostrictive amplifier (Nihon Kohden; AP-601G)
Measured via. Heart rate can be measured using a heart rate monitor (Nihon Kohden; AT
-601G) was synchronized with the blood pressure pulse wave and measured simultaneously. The test drug was administered via a polyethylene cannula inserted into the tail vein in advance.

The above test results are shown in Table 1.

[Effects of the Invention] The compound of the present invention has both a vasodilatory effect based on calcium antagonism and a blood small film collection suppressing effect, and is useful as an antihypertensive agent, a vasodilator, a cerebral circulation improving agent, and an antithrombotic agent.

Patent applicant Fujirebio Co., Ltd. Procedural amendment (voluntary) April 5, 1990 Commissioner of the Japan Patent Office Yoshi 1) Moon Takeshi 1, Indication of the case 1999 Patent Application No. 136208 2, Name of the invention 1.4 -Dihydropyridine derivative 3, Patent applicant address: 4-6-7 Shimoai, Shinjuku-ku, Tokyo 161 "Detailed description of the invention" column 5 of the specification subject to the amendment, Contents of the amendment (1) Specification No. 7 of the present application Delete "2-cyanophenyl group" on page 7, line 7.

(2) On page 12, lines 5 and 6, "N-phenyl-N-methylamino" was corrected to "N-methyl-N-phenylamino 1." )Corrected to ethyl group J, "methyl)aminoethyl group" in line 8
is corrected to "methylamino)ethyl group J.

(3) On page 13, line 4, "-il)" is corrected to "-il)j," and on line 6, "-il)" is corrected to "-il)1."

(4) Delete "r4-(3-nitrophenyl)-3-(3-pyridazinyl)-3-buten-2-one," on page 17, lines 10 to 12.

(5) r4-(3-nitrophenyl)-3-(2-quinolyl)-3butene-2- on page 19, lines 18 to 20
On, delete ".

(6) ll-(2-methoxypyridyl)-4-(3-nitrophenyl)-3-buten-2-one, 3-(6-methoxypyridyl)-4- on page 20, lines 12 to 19. (
3-nitrophenyl)-3buten-2-one, 3-(
2-methylpyridyl)-4-(3-nitrophenyl)-
3-buten-2-one, 3-(1-isoquinolyl)-
4-(3-nitrophenylcou-3-buten-2-one,
” to be deleted.

(7) "N-phenyl-N-methylamino" on page 26, line 7 was corrected to "N-methyl-N-phenylaminoj,"
Correct “diethyl)aminoethyl” in line 9 to rdiethylamino)ethyl 1, and “methyl)” in lines 10 to 11.
Aminoethyl" is corrected to "methylamine)ethyl J.

(8) "-il)" on page 27, line 11.
Corrected ``il)'' in line 13 to r il)j,
Correct "ru)j" in line 15 to "r)j," and correct "-il)" in line 16 to r-il)J.

(9) On page 28, line 20 of the same page, change “carry out in acid” to “
Correct 1 to perform in amide.

(10) "Hydroxy group or halogen atom, methanesulfonyloxy group, benzotriazole-1-oxy group," in p. -1-oxy group".

(11) "(2-naphthyl)5-pyridylpyridine" on page 35, lines 18 to 19 of r(2-naphthyl)-5-
Correct to pyridylpyridine 1.

(12) On page 40, line 14, “N-phenyl-N-methylamino” was corrected to FN-methyl-N-phenylamino 1, and on line 15, “dimethyl)aminoethanol” was changed to rdimethylamine)ethanol 1. Corrected and added “N” on line 16.
-benzyl, N-methyl" is corrected to rN-benzyl-N-methyl1.

(13) On page 41, line 11, “il)” was corrected to r-il)j, and on line 12, “-il)” was corrected to r-il)1.
Correct “ru)” in line 14 to “rru)”, “-yl)” in line 15 to “-yl)j”, and “benzylpyrrolidine” in line 16 to “benzylpyrrolidinej”.

(14) '20 mmole' on page 43, line 7
2. o Correct to mmole3.

(15) r8.43 (LH, ddJ, page 47, line 18)
=4. Hz Hz)J to r8.43(11-(.

dd, J=4.8Hz, 2Hz) Correct to J.

(16) On page 48, lines 1 and 2, "5-pyridylpyridine" is corrected to "r5-(4-pyridyl)pyridine".

<17) r8.13 (2H, d, J
=68Z) J r8.47<2H, d, J=6H7)J
Correct to.

(18) “Pyridyl” on page 54, line 5 of the same page is “pyridyl”
Correct to.

(19) On page 59, line 1 of the same page, insert 290 mg (yield 74%) of the title compound J purified in step 1 before "obtained."

(20) "r3.3Hz" on page 65, line 19 of f5
Corrected to HZJ.

(21) '3-3Hz' on page 66, line 3 of r5) (z
Correct to J.

(22) Delete "°C" on page 70, line 1.

(23) On page 85, line 18, "2-pentene" is corrected to "Venter 2en J.

(24) On page 86, line 5, "2-pentene" is corrected to "penta-2enj."

(25) "Pentagene" in line 1 of page 88 is corrected to rPentagene 1.

(26) On page 89, line 1, "Pentagene" is corrected to rPentagene J.

(27) On page 111, line 1, "r2Hz" is corrected to r5Hzj, and on line 5, "r 2 )1 z" is corrected to r5Hz4.

(28) “3-(pyridyl”) on page 116, line 1
-Corrected to pyridyl 1.

(29) “Methyl 4 (2-J)” on page 117, line 8.
Methyl 4- (Corrected to 2-J.

(30) Correct rdd to rdJ on page 123, line 9.

(31) r7.42 (IH) on page 129, lines 5-7.

d, J=2Hz), 7.44 (IH
,s).

8.07 (LH, t, J=2Hz), 8.
09 (IH, d, J=2Hz)" r7.41 to 7.4
6 <2H, m), 8.07 (IH, d,
J=7Hz>, corrected to 8.09(LH,S)J.

(32) "Molecular sieve 4A1" on page 132, line 5
, correct OmgJ to r molecular sieve 4A 500mgJ.

(33) On page 134, line 3, "3-aminocrotonate j is corrected to 1 methyl 3-aminocrotonate 1."

(34) On page 151, line 3, "3-1 minocrotonate" is corrected to "r-methyl 3-aminocrotonate."

(35) "3-aminocrotonate" on page 153, lines 2 and 3 is corrected to "methyl 3-aminocrotonate."

(36) "Molecular Sieve-4AJ" on page 155, lines 4 to 5 is corrected to r-Molecular Sieve 4AJ.

(37) "Molecular Sieve-4A" on page 157, lines 4 to 5 is corrected to "Molecular Sieve 4AJ."

(38) "Flopen" on page 161, line 3 is corrected to "Propen 1."

(39) Delete "℃" on page 164, line 14.

(40) r8.18 (IH, S> on page 172, line 16)
Insert '8.07 (LH, s), J in front of , line 18 ~
Line 20 “1,4-dihydro-26dimethyl-4-(3
-nitrophenyl)-5(2-pyridyl)pyridine-3
13-cyano-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5
-(2-pyridyl)pyridinej.

(41) Delete "℃" on page 176, line 3.

(42) "Acetyl" on page 178, line 16 is corrected to 13-acetyl 1.

(43) "3-Aminocrotonate" on page 183, lines 4 and 5 is deleted.

Same 1st Page 1 ~ 1st Separate “Table 1” on page 93 Correct as per paper.

Claims (2)

[Claims] (1) 1,4-dihydropyridine derivative (in the formula A
r^1 and Ar^2 are the same or different and are substituted or unsubstituted aromatic hydrocarbon groups or aromatic heterocyclic groups, and R^1 is CO_2R^2, SO_2R^3, CO
R^4, representing CONR_2, CN or NO_2, R
^2 is a hydrogen atom, a straight, branched, or cyclic saturated or unsaturated hydrocarbon group having 2 to 10 carbon atoms, and the group may optionally be a lower alkyl group, a lower alkoxy group, or a substituted or unsubstituted phenoxy group. or may be substituted with a thiophenyl group, a substituted amino group, a substituted or unsubstituted cyclic amino group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted aromatic heterocyclic group, or a trihalomethyl group, R ^3 represents a lower alkyl group, R^4 represents a lower alkyl group or a phenyl group, and R^3 represents a lower alkyl group. ). (2) Claim (1) wherein Ar^1 is an aromatic heterocyclic group.
).